Q (sonnet): show me point mutations in EGFR in lung cancer ▶ read_guide { "uri": "cbioportal://common-pitfalls#16" } ▶ read_guide { "uri": "cbioportal://mutation-frequency-guide" } ▶ list_studies { "search": "lung" } ◀ result ### 16. 🚨 SILENT QUERY SUBSTITUTION ("did you mean...") When the user's wording differs from canonical terminology (e.g. "V600V" looks like "V600E" with a typo, or "point mutation" sounds like "missense"), it is forbidden to silently rewrite the question and answer the rewritten version. Doing so produces an answer that looks confident but is for a different question — the user cannot tell what was changed. #### ❌ Wrong: silently substitute > User: *"Find patients in colorectal cancer with the V600V alteration in BRAF"* > Agent: *(internally treats this as V600E)* "I found 412 samples with BRAF V600E in colorectal studies..." > User: *"What is the most prevalent TP53 mutation in uterine cancer that is not a point mutation?"* > Agent: *(internally treats "point mutation" = "missense", silently excludes only missense)* "The most prevalent non-missense TP53 mutation is..." #### ✅ Correct: answer the literal question, flag any normalization For an unusual-looking variant the user may have typed deliberately: - Query for what was asked, literally. - If 0 rows come back, **explain *why* zero is the expected answer** before suggesting a likely-intended alternative. For synonymous variants (e.g. BRAF V600V, TP53 R175R), the explanation is: *cBioPortal's mutation tables filter out synonymous (silent) variants in most studies, so 0 hits means "filtered upstream", not "no such variant exists in any patient"*. Then ask: *"Did you mean V600E (the canonical activating variant)? Or would you like me to look for V600V in the studies that do retain synonymous calls?"* - If the wording is ambiguous (e.g. "point mutation"), ask the user which definition they meant before querying — do not pick one silently. #### Mutation-type terminology mapping (use this to disambiguate) | User says | Canonical definition | `mutation_type` filter | |---|---|---| | "point mutation" | Any SNV (single-nucleotide variant) — includes missense, nonsense, synonymous, splice-site SNVs | `mutation_type IN ('Missense_Mutation','Nonsense_Mutation','Silent','Splice_Site')` — **but ask the user to confirm scope first** | | "missense" | Single amino-acid substitution that changes the protein | `mutation_type = 'Missense_Mutation'` | | "nonsense" / "stop-gain" | Premature stop codon | `mutation_type = 'Nonsense_Mutation'` | | "synonymous" / "silent" | Nucleotide change with no amino-acid change | `mutation_type = 'Silent'` (**often filtered out of public datasets** — see below) | | "splice site" | Mutation in canonical splice acceptor/donor | `mutation_type = 'Splice_Site'` | | "frameshift" | Indel changing reading frame | `mutation_type IN ('Frame_Shift_Ins','Frame_Shift_Del')` | | "indel" / "in-frame" | In-frame insertion or deletion | `mutation_type IN ('In_Frame_Ins','In_Frame_Del')` | | "truncating" | Anything that disrupts the protein early | `mutation_type IN ('Nonsense_Mutation','Frame_Shift_Ins','Frame_Shift_Del','Splice_Site','Nonstop_Mutation')` | **Synonymous-variant filter. … (785 more chars) ◀ result # Mutation Frequency Analysis Guide ## IMPORTANT: Reporting Mutation Frequencies - **ALWAYS report frequencies as percentages**, not raw counts: `frequency = (altered_samples / total_profiled_samples) × 100` - For quick frequency lookups, **prefer the TCGA Pan-Cancer Atlas study first**, then offer to expand to other studies - When reporting across multiple studies, show **ranges** (e.g., "TP53 is mutated in 30–60% of samples") rather than a single average - **NEVER** sum mutation events across studies to compute an aggregate frequency — this can exceed 100% due to double-counting - Warn users that samples may overlap across cohorts (e.g., MSK studies may share patients) - **Choose and state the counting unit**: use patient-level frequencies for prevalence/rate questions unless the user explicitly asks for samples; use sample-level frequencies when the user asks about samples. - **For "across cancer types" questions**, jump to the [Cross-Cancer-Type Mutation Frequency](#cross-cancer-type-mutation-frequency) section below — there is one correct recipe and several common wrong ones. ## Counting Unit: Samples vs Patients Before answering any mutation count or frequency question, decide whether the unit is samples or patients and state that choice in the answer. | User wording | Counting unit | |--------------|---------------| | "prevalence", "rate", "fraction of patients", "patients with", "how common is" | Patient-level: `COUNT(DISTINCT patient_unique_id)` | | "samples", "specimens", "biopsies", sample-level cohort composition | Sample-level: `COUNT(DISTINCT sample_unique_id)` | | Ambiguous | Ask, or default to patient-level for prevalence/rate language and say so | ### Cross-study sample-count caveat When an answer touches more than one study and reports a sample count, prepend a one-line caveat: > Sample IDs are unique within cBioPortal study prefixes, not guaranteed biological-sample identifiers across studies; overlapping cohorts can count the same patient/sample more than once. Prefer one of these safer approaches: - Use a shipped `cancer_study_query_preferences` cohort such as `pan_cancer_tcga` or `all_studies_non_redundant`. - Restrict to one named study. - Aggregate by `patient_unique_id` when the biological question is patient prevalence. ## STOP rule: a frequency above 100% means your query is wrong If your query returns a frequency over 100%, **do not try to debug or explain the data inconsistency to the user**. The cause is always one of these query bugs: - Summing mutation events instead of `COUNT(DISTINCT sample_unique_id)` for the numerator - Using a study-wide sample count as the denominator instead of the gene-specific profiled count - Cross-study aggregation where the same biological sample appears under multiple `sample_unique_id` values (e.g., MSK-IMPACT and MSK-CHORD share patients) - **Joining the profiled CTE through `gene_panel` / `gene_panel_list` without a WES branch.** `gene_panel_id = 'WES'` is *not* a row in … (36467 more chars) ◀ result {"result":[{"cancer_study_identifier":"msk_met_2021","name":"MSK MetTropism (MSK, Cell 2021)","type_of_cancer_id":"mixed","sample_count":25775,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=msk_met_2021"},{"cancer_study_identifier":"luad_mskcc_2023_met_organotropism","name":"Lung Adenocarcinoma Met Organotropism (MSK, Cancer Cell 2023)","type_of_cancer_id":"luad","sample_count":2653,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=luad_mskcc_2023_met_organotropism"},{"cancer_study_identifier":"nsclc_ctdx_msk_2022","name":"Metastatic Non-Small Cell Lung Cancer (MSK, Nature Medicine 2022)","type_of_cancer_id":"nsclc","sample_count":2621,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=nsclc_ctdx_msk_2022"},{"cancer_study_identifier":"nsclc_tcga_broad_2016","name":"Pan-Lung Cancer (TCGA, Nat Genet 2016)","type_of_cancer_id":"nsclc","sample_count":1144,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=nsclc_tcga_broad_2016"},{"cancer_study_identifier":"lung_msk_2017","name":"Non-Small Cell Cancer (MSK, Cancer Discov 2017)","type_of_cancer_id":"luad","sample_count":915,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lung_msk_2017"},{"cancer_study_identifier":"luad_mskcc_2020","name":"Lung Adenocarcinoma (MSK, J Thorac Oncol 2020)","type_of_cancer_id":"luad","sample_count":604,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=luad_mskcc_2020"},{"cancer_study_identifier":"luad_tcga","name":"Lung Adenocarcinoma (TCGA, Firehose Legacy)","type_of_cancer_id":"luad","sample_count":586,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=luad_tcga"},{"cancer_study_identifier":"luad_tcga_gdc","name":"Lung Adenocarcinoma (TCGA GDC, 2025)","type_of_cancer_id":"luad","sample_count":571,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=luad_tcga_gdc"},{"cancer_study_identifier":"luad_tcga_pan_can_atlas_2018","name":"Lung Adenocarcinoma (TCGA, PanCancer Atlas)","type_of_cancer_id":"luad","sample_count":566,"has_guide":true,"url":"https://www.cbioportal.org/study/summary?id=luad_tcga_pan_can_atlas_2018"},{"cancer_study_identifier":"lusc_tcga","name":"Lung Squamous Cell Carcinoma (TCGA, Firehose Legacy)","type_of_cancer_id":"lusc","sample_count":511,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lusc_tcga"},{"cancer_study_identifier":"lusc_tcga_gdc","name":"Lung Squamous Cell Carcinoma (TCGA GDC, 2025)","type_of_cancer_id":"lusc","sample_count":503,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lusc_tcga_gdc"},{"cancer_study_identifier":"lusc_tcga_pan_can_atlas_2018","name":"Lung Squamous Cell Carcinoma (TCGA, PanCancer Atlas)","type_of_cancer_id":"lusc","sample_count":487,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lusc_tcga_pan_can_atlas_2018"},{"cancer_study_identifier":"nsclc_tracerx_2017","name":"Non-Small Cell Lung Cancer (TRACERx, NEJM & N … (1826 more chars) ▶ clickhouse_run_select_query { "query": "SELECT 'LUAD' AS histology, mutation_variant, mutation_type, altered_samples, profiled_samples, frequency_pct, total_mutation_events FROM gene_mutation_variants_in_study(study = 'luad_tcga_pan_can_atlas_2018', gene = 'EGFR') WHERE mutation_type IN ('Missense_Mutation','Nonsense_Mutation','Silent','Splice_Site') ORDER BY altered_samples DESC" } ▶ clickhouse_run_select_query { "query": "SELECT 'LUSC' AS histology, mutation_variant, mutation_type, altered_samples, profiled_samples, frequency_pct, total_mutation_events FROM gene_mutation_variants_in_study(study = 'lusc_tcga_pan_can_atlas_2018', gene = 'EGFR') WHERE mutation_type IN ('Missense_Mutation','Nonsense_Mutation','Silent','Splice_Site') ORDER BY altered_samples DESC" } ◀ result {"rows":[{"histology":"LUAD","mutation_variant":"L858R","mutation_type":"Missense_Mutation","altered_samples":23,"profiled_samples":566,"frequency_pct":4.1,"total_mutation_events":23},{"histology":"LUAD","mutation_variant":"L861Q","mutation_type":"Missense_Mutation","altered_samples":3,"profiled_samples":566,"frequency_pct":0.5,"total_mutation_events":3},{"histology":"LUAD","mutation_variant":"S768I","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2},{"histology":"LUAD","mutation_variant":"L62R","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2},{"histology":"LUAD","mutation_variant":"T790M","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2},{"histology":"LUAD","mutation_variant":"G719A","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2},{"histology":"LUAD","mutation_variant":"G719C","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUAD","mutation_variant":"R222L","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUAD","mutation_variant":"E545Q","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUAD","mutation_variant":"R1052I","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUAD","mutation_variant":"G901V","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUAD","mutation_variant":"L833F","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUAD","mutation_variant":"L387M","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUAD","mutation_variant":"Q486*","mutation_type":"Nonsense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUAD","mutation_variant":"V300M","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUAD","mutation_variant":"L833V","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUAD","mutation_variant":"I759N","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":566,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUAD","mutation_variant":"L907M"," … (1682 more chars) ◀ result {"rows":[{"histology":"LUSC","mutation_variant":"L861Q","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":484,"frequency_pct":0.4,"total_mutation_events":2},{"histology":"LUSC","mutation_variant":"G627*","mutation_type":"Nonsense_Mutation","altered_samples":1,"profiled_samples":484,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUSC","mutation_variant":"S229C","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":484,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUSC","mutation_variant":"V843L","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":484,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUSC","mutation_variant":"G87C","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":484,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUSC","mutation_variant":"Y1138C","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":484,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUSC","mutation_variant":"P192R","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":484,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUSC","mutation_variant":"S720C","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":484,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUSC","mutation_variant":"P589L","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":484,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUSC","mutation_variant":"P1019L","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":484,"frequency_pct":0.2,"total_mutation_events":1},{"histology":"LUSC","mutation_variant":"X210_splice","mutation_type":"Splice_Site","altered_samples":1,"profiled_samples":484,"frequency_pct":0.2,"total_mutation_events":1}]} ▶ resolve_and_route { "studyIds": [ "luad_tcga_pan_can_atlas_2018", "lusc_tcga_pan_can_atlas_2018" ] } ◀ result {"success":true,"message":"Found 2 matching studies. Pick the best match (prefer TCGA → prefer PanCancer Atlas), use its metadata to call the appropriate navigation tool(s) and generate URLs immediately. Present other studies as alternatives.","data":{"totalCount":2,"studiesWithMetadata":[{"studyId":"luad_tcga_pan_can_atlas_2018","name":"Lung Adenocarcinoma (TCGA, PanCancer Atlas)","sampleCount":566,"studyViewUrl":"https://www.cbioportal.org/study?id=luad_tcga_pan_can_atlas_2018","metadata":{"clinicalAttributeIds":["AGE","AJCC_PATHOLOGIC_TUMOR_STAGE","AJCC_STAGING_EDITION","ANEUPLOIDY_SCORE","BUFFA_HYPOXIA_SCORE","CANCER_TYPE","CANCER_TYPE_ACRONYM","CANCER_TYPE_DETAILED","DAYS_LAST_FOLLOWUP","DAYS_TO_BIRTH","DAYS_TO_INITIAL_PATHOLOGIC_DIAGNOSIS","DFS_MONTHS","DFS_STATUS","DSS_MONTHS","DSS_STATUS","ETHNICITY","FORM_COMPLETION_DATE","FRACTION_GENOME_ALTERED","GENETIC_ANCESTRY_LABEL","GRADE","HISTORY_NEOADJUVANT_TRTYN","ICD_10","ICD_O_3_HISTOLOGY","ICD_O_3_SITE","INFORMED_CONSENT_VERIFIED","IN_PANCANPATHWAYS_FREEZE","MSI_SCORE_MANTIS","MSI_SENSOR_SCORE","MUTATION_COUNT","NEW_TUMOR_EVENT_AFTER_INITIAL_TREATMENT","ONCOTREE_CODE","OS_MONTHS","OS_STATUS","OTHER_PATIENT_ID","PATH_M_STAGE","PATH_N_STAGE","PATH_T_STAGE","PERSON_NEOPLASM_CANCER_STATUS","PFS_MONTHS","PFS_STATUS","PRIMARY_LYMPH_NODE_PRESENTATION_ASSESSMENT","PRIOR_DX","RACE","RADIATION_THERAPY","RAGNUM_HYPOXIA_SCORE","SAMPLE_COUNT","SAMPLE_TYPE","SEX","SOMATIC_STATUS","SUBTYPE","TBL_SCORE","TISSUE_PROSPECTIVE_COLLECTION_INDICATOR","TISSUE_RETROSPECTIVE_COLLECTION_INDICATOR","TISSUE_SOURCE_SITE","TISSUE_SOURCE_SITE_CODE","TMB_NONSYNONYMOUS","TUMOR_TISSUE_SITE","TUMOR_TYPE","WEIGHT","WINTER_HYPOXIA_SCORE"],"molecularProfileIds":["luad_tcga_pan_can_atlas_2018_gistic","luad_tcga_pan_can_atlas_2018_log2CNA","luad_tcga_pan_can_atlas_2018_mutations","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_ref_normal_Zscores","luad_tcga_pan_can_atlas_2018_rppa","luad_tcga_pan_can_atlas_2018_rppa_Zscores","luad_tcga_pan_can_atlas_2018_structural_variants"],"genericAssayProfiles":["luad_tcga_pan_can_atlas_2018_armlevel_cna","luad_tcga_pan_can_atlas_2018_genetic_ancestry","luad_tcga_pan_can_atlas_2018_methylation_hm27_hm450_merge","luad_tcga_pan_can_atlas_2018_methylation_hm450"],"heatmapProfileIds":["luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_ref_normal_Zscores","luad_tcga_pan_can_atlas_2018_rppa_Zscores"],"availableComparisonTabs":["overlap","clinical","survival","alterations","mutations","mrna","protein","generic_assay_armlevel_cna","generic_assay_genetic_ancestry","generic_assay_methylation"]}},{"studyId":"lusc_tcga_pan_can_atlas_2018","name":"Lung Squamous Cell … (2585 more chars) ▶ navigate_to_results_view { "studyIds": [ "luad_tcga_pan_can_atlas_2018" ], "genes": [ "EGFR: MUT = MISSENSE MUT = NONSENSE MUT = SPLICE" ], "tab": "mutations" } ◀ result {"success":true,"message":"Navigating to https://www.cbioportal.org/results/mutations?cancer_study_list=luad_tcga_pan_can_atlas_2018&gene_list=EGFR%3A+MUT+%3D+MISSENSE+MUT+%3D+NONSENSE+MUT+%3D+SPLICE&case_set_id=luad_tcga_pan_can_atlas_2018_all","url":"https://www.cbioportal.org/results/mutations?cancer_study_list=luad_tcga_pan_can_atlas_2018&gene_list=EGFR%3A+MUT+%3D+MISSENSE+MUT+%3D+NONSENSE+MUT+%3D+SPLICE&case_set_id=luad_tcga_pan_can_atlas_2018_all","data":{"studyIds":["luad_tcga_pan_can_atlas_2018"],"studies":[{"studyId":"luad_tcga_pan_can_atlas_2018","name":"Lung Adenocarcinoma (TCGA, PanCancer Atlas)","sampleCount":566}],"genes":["EGFR"],"caseSetId":"luad_tcga_pan_can_atlas_2018_all","pageDescription":"Detailed mutation table with lollipop plot showing mutation positions, types, and frequencies for queried genes."}} ▶ navigate_to_results_view { "studyIds": [ "lusc_tcga_pan_can_atlas_2018" ], "genes": [ "EGFR: MUT = MISSENSE MUT = NONSENSE MUT = SPLICE" ], "tab": "mutations" } ◀ result {"success":true,"message":"Navigating to https://www.cbioportal.org/results/mutations?cancer_study_list=lusc_tcga_pan_can_atlas_2018&gene_list=EGFR%3A+MUT+%3D+MISSENSE+MUT+%3D+NONSENSE+MUT+%3D+SPLICE&case_set_id=lusc_tcga_pan_can_atlas_2018_all","url":"https://www.cbioportal.org/results/mutations?cancer_study_list=lusc_tcga_pan_can_atlas_2018&gene_list=EGFR%3A+MUT+%3D+MISSENSE+MUT+%3D+NONSENSE+MUT+%3D+SPLICE&case_set_id=lusc_tcga_pan_can_atlas_2018_all","data":{"studyIds":["lusc_tcga_pan_can_atlas_2018"],"studies":[{"studyId":"lusc_tcga_pan_can_atlas_2018","name":"Lung Squamous Cell Carcinoma (TCGA, PanCancer Atlas)","sampleCount":487}],"genes":["EGFR"],"caseSetId":"lusc_tcga_pan_can_atlas_2018_all","pageDescription":"Detailed mutation table with lollipop plot showing mutation positions, types, and frequencies for queried genes."}} ═ answer (success) [EGFR point mutations — Lung Adenocarcinoma (TCGA, PanCancer Atlas)](https://www.cbioportal.org/results/mutations?cancer_study_list=luad_tcga_pan_can_atlas_2018&gene_list=EGFR%3A+MUT+%3D+MISSENSE+MUT+%3D+NONSENSE+MUT+%3D+SPLICE&case_set_id=luad_tcga_pan_can_atlas_2018_all) — lollipop plot of missense/nonsense/splice-site variants across all 566 samples. [EGFR point mutations — Lung Squamous Cell Carcinoma (TCGA, PanCancer Atlas)](https://www.cbioportal.org/results/mutations?cancer_study_list=lusc_tcga_pan_can_atlas_2018&gene_list=EGFR%3A+MUT+%3D+MISSENSE+MUT+%3D+NONSENSE+MUT+%3D+SPLICE&case_set_id=lusc_tcga_pan_can_atlas_2018_all) — 487 samples. Both links open the Mutations tab pre-filtered to substitution-type point mutations, excluding indels and copy-number events. **Note:** If by "lung cancer" you meant a broader NSCLC cohort (e.g., MSK-IMPACT clinical cohorts) or wanted to include the classic exon 19 deletion alongside point mutations, or if "point mutation" should mean missense-only in your context, let me know and I'll rerun with the adjusted scope.