Genomics

## Setup On first use, read `setup.md` for integration guidelines. Ask user consent before creating `~/genomics/` workspace. ## When to Use User has processed genomic data (VCF files) and needs clinical interpretation. Agent handles variant classification, pharmacogenomics recommendations, and annotation lookup. NOT for raw data processing — use `bioinformatics` skill for alignment and variant calling. ## Architecture Memory lives in `~/genomics/`. See `memory-template.md` for structure. ``` ~/genomics/ ├── memory.md # Context + preferences + interpretation history └── cases/ # Active interpretation cases ``` ## Quick Reference | Topic | File | |-------|------| | Setup process | `setup.md` | | Memory template | `memory-template.md` | ## Core Rules ### 1. Classify Variants Using ACMG Guidelines Every variant needs systematic classification: | Category | Criteria | |----------|----------| | Pathogenic | PVS1, PS1-4, PM1-6, PP1-5 weighted | | Likely Pathogenic | Strong + moderate evidence | | VUS | Insufficient or conflicting evidence | | Likely Benign | BS1-4, BP1-7 weighted | | Benign | Strong benign evidence | **Never classify without evidence.** State "insufficient data" when appropriate. ### 2. Check Population Frequency First Before clinical interpretation, verify frequency: | Source | Use For | |--------|---------| | gnomAD v4 | Global population frequency | | gnomAD non-cancer | Somatic analysis | | Population-specific | Ancestry-appropriate filtering | **MAF >1% in any population = likely benign for rare disease.** ### 3. Cross-Reference Multiple Databases | Database | Information | |----------|-------------| | ClinVar | Clinical classifications + submitter evidence | | OMIM | Gene-disease relationships | | HGMD | Literature-reported mutations | | UniProt | Protein function + domains | **Single-source interpretation is insufficient.** Triangulate evidence. ### 4. Report Pharmacogenomics Actionably For drug-gene interactions, provide: - Diplotype (e.g., CYP2D6 *1/*4) - Predicted phenotype (poor/intermediate/normal/ultra-rapid metabolizer) - Drug list affected - Dosing guidance (CPIC/DPWG when available) ### 5. Separate Germline from Somatic Context | Context | Key Differences | |---------|-----------------| | Germline | Family implications, carrier testing, predictive | | Somatic | Tumor-specific, therapy selection, no inheritance | **Always state which context you're interpreting.** ### 6. Acknowledge Uncertainty - Novel variants often lack evidence - VUS ≠ benign — requires ongoing monitoring - Reclassification happens (ClinVar updates monthly) - Computational predictions are supportive, not definitive ## Pharmacogenomics Reference ### High-Priority Drug-Gene Pairs (CPIC Level A) | Gene | Drugs | Clinical Action | |------|-------|-----------------| | CYP2D6 | Codeine, tramadol, tamoxifen, SSRIs | Dosing/alternative | | CYP2C19 | Clopidogrel, PPIs, voriconazole | Dosing/alternative | | CYP2C9 + VKORC1 | Warfarin | Dosing algorithm | | DPYD | Fluorouracil, capecitabine | Dose reduction/avoid | | TPMT + NUDT15 | Azathioprine, mercaptopurine | Dose reduction | | HLA-B*57:01 | Abacavir | Contraindication | | HLA-B*15:02 | Carbamazepine | Contraindication (Asian ancestry) | | SLCO1B1 | Simvastatin | Dose cap/alternative statin | | G6PD | Rasburicase, primaquine | Contraindication | | CYP3A5 | Tacrolimus | Dosing adjustment | ### Phenotype Interpretation | Metabolizer Status | Meaning | Typical Action | |--------------------|---------|----------------| | Poor (PM) | Little/no enzyme activity | Alternative drug or dose ↓↓ | | Intermediate (IM) | Reduced activity | Consider dose ↓ | | Normal (NM) | Expected activity | Standard dosing | | Rapid/Ultra-rapid (UM) | Increased activity | Dose ↑ or alternative | ## Annotation Resources | Resource | URL | Content | |----------|-----|---------| | ClinVar | ncbi.nlm.nih.gov/clinvar | Clinical variant classifications | | gnomAD | gnomad.broadinstitute.org | Population frequencies | | OMIM | omim.org | Gene-disease relationships | | PharmGKB | pharmgkb.org | Drug-gene annotations | | CPIC | cpicpgx.org | Pharmacogenomics guidelines | | ClinGen | clinicalgenome.org | Gene-disease validity | | Franklin | franklin.genoox.com | Variant interpretation aid | | VarSome | varsome.com | ACMG auto-classification | ## Common Interpretation Traps - **Ignoring population specificity** — Variants common in African populations may look rare in European-biased databases - **Trusting single ClinVar submitter** — Check submitter count and review status (≥2 submitters, no conflict preferred) - **Conflating computational prediction with evidence** — CADD/REVEL are supportive, not diagnostic - **Missing compound heterozygosity** — Two VUS in trans can be pathogenic together - **Outdated database versions** — gnomAD v4 has 800K+ exomes vs v2's 125K - **Ignoring gene-level constraint** — pLI/LOEUF scores indicate tolerance to loss-of-function ## External Endpoints This skill does NOT automatically call external APIs. All database references are for manual lookup: | Resource | When Used | Data Sent | |----------|-----------|-----------| | ClinVar, gnomAD, OMIM | User manually visits | None by this skill | | PharmGKB, CPIC | User manually visits | None by this skill | | VarSome, Franklin | User manually visits | None by this skill | **No automatic network requests.** The skill provides URLs and guidance for manual lookup only. ## Security & Privacy **Data that stays local:** - All interpretation work runs locally - No variant data sent externally by this skill - No automatic API calls to any database **This skill does NOT:** - Make network requests automatically - Upload patient variants anywhere - Connect to databases without explicit user action - Store identifiable genomic information outside ~/genomics/ ## Related Skills Install with `clawhub install <slug>` if user confirms: - `medicine` — clinical decision support - `biology` — molecular mechanisms - `chemistry` — drug metabolism pathways - `health` — patient care context ## Feedback - If useful: `clawhub star genomics` - Stay updated: `clawhub sync`