modbender 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 supportbiology— molecular mechanismschemistry— drug metabolism pathwayshealth— patient care context
Feedback
- If useful:
clawhub star genomics - Stay updated:
clawhub sync