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clinvar-database

Research
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Utilities for querying the NCBI ClinVar database to retrieve variant records, clinical significance, and phenotype relationships; use when searching variants by gene/condition/significance, interpreting Pathogenic/Benign/VUS classifications, or annotating VCF files with ClinVar annotations.

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How to use this skill

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Source: https://github.com/aipoch/medical-research-skills

When to Use

  • You need to find ClinVar variant records by gene, condition/phenotype, or clinical significance (e.g., BRCA1 + pathogenic).
  • You want to interpret a variant’s clinical significance (Pathogenic/Benign/VUS) and review status for reporting or triage.
  • You need to annotate a VCF with ClinVar identifiers and interpretation fields as part of a variant annotation pipeline.
  • You want to perform bulk retrieval of ClinVar datasets for offline analysis or periodic database refresh.
  • You are building a workflow that relies on NCBI E-utilities to programmatically query ClinVar.

Key Features

  • ClinVar search via NCBI E-utilities using flexible query terms (gene/condition/significance).
  • Clinical interpretation retrieval, including clinical significance categories and review status.
  • VCF annotation workflow integration (leveraging bcftools) to enrich variants with ClinVar data.
  • Bulk data access through ClinVar FTP downloads for large-scale processing.
  • Reference documentation:
    • API details: references/api_reference.md
    • Clinical significance definitions: references/clinical_significance.md

Dependencies

  • Python >=3.8
  • requests (Python package)
  • bcftools (system dependency; required for VCF annotation)
  • pandas (Python package; optional for downstream data processing)

Example Usage

1) Search ClinVar for pathogenic variants in a gene

python scripts/search.py --term "BRCA1[gene] AND pathogenic[CLNSIG]"

2) Annotate a VCF with ClinVar data

python scripts/annotate.py --input input.vcf --output annotated.vcf

Implementation Details

  • Search (scripts/search.py)

    • Uses NCBI E-utilities to query ClinVar with a user-provided --term.
    • The query term supports ClinVar/Entrez syntax (e.g., BRCA1[gene], pathogenic[CLNSIG]) to filter by gene and clinical significance.
    • Output is expected to include matching ClinVar records/identifiers suitable for follow-up interpretation or annotation.

  • Interpretation fields

    • Clinical significance values (e.g., Pathogenic/Benign/VUS) and related interpretation guidance follow ClinVar conventions; see references/clinical_significance.md.
    • Review status (e.g., level of evidence/review) is retrieved alongside significance where available.

  • VCF annotation (scripts/annotate.py)

    • Takes an input VCF (--input) and produces an annotated VCF (--output).
    • Integrates with bcftools to add ClinVar-derived annotations to variant records (requires bcftools installed and available on PATH).
    • Designed for pipeline use: deterministic input/output files and command-line parameters.

  • Bulk downloads

    • Supports obtaining ClinVar datasets via FTP for offline indexing/annotation workflows.
    • Recommended when you need reproducible, high-throughput annotation without repeated API calls.