Q (haiku): How many samples are there that have any of these mutations in SEPHS1: p.Arg371Trp, p.Arg371Gln, p.Arg371Gly?

▶ read_guide
{
 "uri": "cbioportal://mutation-frequency-guide"
}

◀ 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 … (35166 more chars)

▶ clickhouse_list_tables
{}

▶ clickhouse_list_table_columns
{
 "table": "genomic_event_derived"
}

◀ result
{"tables":[{"name":"allele_specific_copy_number"},{"name":"alteration_driver_annotation"},{"name":"cancer_study"},{"name":"cancer_study_query_preferences"},{"name":"cancer_study_tags"},{"name":"cbioportal_sequence_state"},{"name":"clinical_attribute_counts"},{"name":"clinical_attribute_meta"},{"name":"clinical_data_derived"},{"name":"clinical_event"},{"name":"clinical_event_data"},{"name":"clinical_event_data_derived"},{"name":"clinical_event_derived"},{"name":"clinical_patient"},{"name":"clinical_sample"},{"name":"cna_event"},{"name":"cna_panel_gene_coverage"},{"name":"cna_wes_coverage"},{"name":"co_altered_genes_in_study"},{"name":"copy_number_seg"},{"name":"copy_number_seg_file"},{"name":"gene"},{"name":"gene_alias"},{"name":"gene_alteration_frequency_by_cancer_type"},{"name":"gene_cna_distribution_in_study"},{"name":"gene_mutation_frequency_by_cancer_type"},{"name":"gene_mutation_frequency_in_studies"},{"name":"gene_mutation_frequency_in_study"},{"name":"gene_mutation_variants_in_study"},{"name":"gene_pair_coexpression"},{"name":"gene_panel"},{"name":"gene_panel_list"},{"name":"gene_panel_to_gene_derived"},{"name":"generic_assay_data_derived"},{"name":"generic_assay_meta_derived"},{"name":"generic_assay_profile_entity_derived"},{"name":"generic_entity_properties"},{"name":"geneset"},{"name":"geneset_gene"},{"name":"geneset_hierarchy_leaf"},{"name":"geneset_hierarchy_node"},{"name":"genetic_alteration"},{"name":"genetic_alteration_derived"},{"name":"genetic_entity"},{"name":"genetic_profile"},{"name":"genetic_profile_link"},{"name":"genetic_profile_samples"},{"name":"genomic_event_derived"},{"name":"gistic"},{"name":"gistic_to_gene"},{"name":"info"},{"name":"mut_sig"},{"name":"mutation"},{"name":"mutation_count_by_keyword"},{"name":"mutation_derived"},{"name":"mutation_event"},{"name":"mutation_panel_gene_coverage"},{"name":"mutation_wes_coverage"},{"name":"patient"},{"name":"reference_genome"},{"name":"reference_genome_gene"},{"name":"resource_definition"},{"name":"resource_patient"},{"name":"resource_sample"},{"name":"resource_study"},{"name":"sample"},{"name":"sample_cna_event"},{"name":"sample_derived"},{"name":"sample_list"},{"name":"sample_list_list"},{"name":"sample_profile"},{"name":"sample_to_gene_panel_derived"},{"name":"structural_variant"},{"name":"sv_panel_gene_coverage"},{"name":"sv_wes_coverage"},{"name":"top_cna_genes_in_study"},{"name":"top_mutated_genes_in_cohort"},{"name":"top_mutated_genes_in_study"},{"name":"top_sv_genes_in_study"},{"name":"treatment_counts_in_study"},{"name":"treatment_regimens_in_study"},{"name":"type_of_cancer"}]}

◀ result
{"columns":[{"name":"sample_unique_id","type":"String"},{"name":"hugo_gene_symbol","type":"String","comment":"HUGO gene symbol (e.g., TP53, KRAS, BRAF). Use for gene-specific queries."},{"name":"entrez_gene_id","type":"Int32"},{"name":"gene_panel_stable_id","type":"LowCardinality(String)"},{"name":"cancer_study_identifier","type":"LowCardinality(String)"},{"name":"genetic_profile_stable_id","type":"LowCardinality(String)"},{"name":"variant_type","type":"LowCardinality(String)","comment":"Type of genomic event: \"mutation\" for SNVs/indels, \"cna\" for copy number alterations, \"structural_variant\" for SVs. Always filter by this."},{"name":"mutation_variant","type":"String","comment":"Protein change notation (e.g., p.V600E, p.R175H). Use for specific variant queries. \"NA\" for non-mutation events."},{"name":"mutation_type","type":"LowCardinality(String)"},{"name":"mutation_status","type":"LowCardinality(String)","comment":"For mutations: Somatic, Germline, UNKNOWN, or UNCALLED. Filter mutation_status != \"UNCALLED\" to exclude uncertain calls. Include all other statuses."},{"name":"driver_filter","type":"LowCardinality(String)"},{"name":"driver_filter_annotation","type":"String"},{"name":"driver_tiers_filter","type":"LowCardinality(String)"},{"name":"driver_tiers_filter_annotation","type":"String"},{"name":"cna_alteration","type":"Nullable(Int8)","comment":"Copy number alteration: only 2 = amplification (AMP) and -2 = deep deletion (HOMDEL) are stored. Shallow deletion (-1), diploid (0) and gain (1) are not in this table; query genetic_alteration_derived WHERE profile_type = 'gistic' (alteration_value is a String, e.g. '-1'). NULL for non-CNA events."},{"name":"cna_cytoband","type":"String"},{"name":"sv_event_info","type":"String"},{"name":"patient_unique_id","type":"String"},{"name":"off_panel","type":"Bool","comment":"Boolean: 1 = mutation outside gene panel coverage (off-panel), 0 = within panel (on-panel). Filter off_panel = 0 for reliable frequency calculations."}]}

▶ clickhouse_run_select_query
{
 "query": "
SELECT 
    COUNT(DISTINCT sample_unique_id) AS sample_count,
    COUNT(*) AS mutation_events,
    COUNT(DISTINCT cancer_study_identifier) AS study_count,
    COUNT(DISTINCT patient_unique_id) AS patient_count
FROM genomic_event_derived
WHERE hugo_gene_symbol = 'SEPHS1'
  AND variant_type = 'mutation'
  AND mutation_status != 'UNCALLED'
  AND mutation_variant IN ('p.Arg371Trp', 'p.Arg371Gln', 'p.Arg371Gly')
",
 "max_rows": 100
}

◀ result
{"rows":[{"sample_count":0,"mutation_events":0,"study_count":0,"patient_count":0}]}

▶ clickhouse_run_select_query
{
 "query": "
SELECT 
    mutation_variant,
    COUNT(DISTINCT sample_unique_id) AS sample_count,
    COUNT(*) AS mutation_events
FROM genomic_event_derived
WHERE hugo_gene_symbol = 'SEPHS1'
  AND variant_type = 'mutation'
  AND mutation_status != 'UNCALLED'
GROUP BY mutation_variant
ORDER BY sample_count DESC
LIMIT 20
",
 "max_rows": 100
}

◀ result
{"rows":[{"mutation_variant":"E13K","sample_count":13,"mutation_events":13},{"mutation_variant":"A245V","sample_count":12,"mutation_events":12},{"mutation_variant":"R362H","sample_count":11,"mutation_events":11},{"mutation_variant":"A262T","sample_count":11,"mutation_events":11},{"mutation_variant":"R371Q","sample_count":9,"mutation_events":9},{"mutation_variant":"R19Q","sample_count":8,"mutation_events":8},{"mutation_variant":"C104Y","sample_count":8,"mutation_events":8},{"mutation_variant":"V196M","sample_count":7,"mutation_events":7},{"mutation_variant":"Q39*","sample_count":6,"mutation_events":6},{"mutation_variant":"X218_splice","sample_count":6,"mutation_events":6},{"mutation_variant":"P34L","sample_count":6,"mutation_events":6},{"mutation_variant":"V302M","sample_count":6,"mutation_events":6},{"mutation_variant":"Q51*","sample_count":6,"mutation_events":6},{"mutation_variant":"T29I","sample_count":6,"mutation_events":6},{"mutation_variant":"E339K","sample_count":6,"mutation_events":6},{"mutation_variant":"G389R","sample_count":5,"mutation_events":5},{"mutation_variant":"X100_splice","sample_count":5,"mutation_events":5},{"mutation_variant":"D134N","sample_count":5,"mutation_events":5},{"mutation_variant":"E219D","sample_count":5,"mutation_events":5},{"mutation_variant":"R137K","sample_count":5,"mutation_events":5}]}

▶ clickhouse_run_select_query
{
 "query": "
SELECT 
    mutation_variant,
    COUNT(DISTINCT sample_unique_id) AS sample_count,
    COUNT(*) AS mutation_events,
    COUNT(DISTINCT cancer_study_identifier) AS study_count
FROM genomic_event_derived
WHERE hugo_gene_symbol = 'SEPHS1'
  AND variant_type = 'mutation'
  AND mutation_status != 'UNCALLED'
  AND mutation_variant IN ('R371W', 'R371Q', 'R371G')
GROUP BY mutation_variant
ORDER BY sample_count DESC
",
 "max_rows": 100
}

◀ result
{"rows":[{"mutation_variant":"R371Q","sample_count":9,"mutation_events":9,"study_count":7},{"mutation_variant":"R371W","sample_count":2,"mutation_events":2,"study_count":2}]}

▶ clickhouse_run_select_query
{
 "query": "
SELECT 
    COUNT(DISTINCT sample_unique_id) AS total_samples_with_any_mutation,
    COUNT(*) AS total_mutation_events,
    COUNT(DISTINCT patient_unique_id) AS total_patients,
    COUNT(DISTINCT cancer_study_identifier) AS studies_with_mutations
FROM genomic_event_derived
WHERE hugo_gene_symbol = 'SEPHS1'
  AND variant_type = 'mutation'
  AND mutation_status != 'UNCALLED'
  AND mutation_variant IN ('R371W', 'R371Q', 'R371G')
",
 "max_rows": 100
}

◀ result
{"rows":[{"total_samples_with_any_mutation":11,"total_mutation_events":11,"total_patients":11,"studies_with_mutations":9}]}

═ answer (success)
## Results

**11 samples** carry one of these SEPHS1 Arg371 mutations:

| Mutation | Samples | Mutation Events |
|----------|---------|-----------------|
| R371Q (p.Arg371Gln) | 9 | 9 |
| R371W (p.Arg371Trp) | 2 | 2 |
| R371G (p.Arg371Gly) | 0 | 0 |

**Summary:**
- **Total samples with any of these mutations: 11**
- Total mutation events: 11 (no sample carries multiple of these mutations)
- Total patients affected: 11 (sample and patient counts are identical, indicating one sample per patient)
- Number of studies with these mutations: 9

**Note:** The database uses shorthand mutation notation (e.g., `R371Q` for p.Arg371Gln) rather than the full HGVS `p.` format you provided. R371G (p.Arg371Gly) does not appear in cBioPortal's current dataset.