ncbi-clinvar

name	ncbi_clinvar
description	Query NCBI ClinVar for variant clinical significance. Search by gene/condition/CLNSIG, interpret pathogenicity, use E-utilities or FTP; annotate VCFs. Use project tools in src.tools.database.ncbi.
license	Unknown
metadata	{"skill-author":"VenusFactory2"}

ClinVar Database (NCBI)

Overview

ClinVar is NCBI's archive of relationships between human genetic variants and phenotypes, with supporting evidence. In this project the agent exposes one compound download tool (download_ncbi_clinvar_variants) that searches by term, retrieves variant IDs, and saves results to JSON. For finer control, ncbi_operations.py also provides atomic ClinVar E-utilities download/query functions (esearch, esummary, efetch), and the low-level module ncbi_clinvar.py provides term builders and FTP helpers. All download/query functions return rich JSON {status, file_info/content, content_preview, biological_metadata, execution_context}.

When to Use This Skill

• Searching for variants by gene, condition, or clinical significance
• Interpreting clinical significance (pathogenic, benign, VUS); see references/clinical_significance.md
• Accessing ClinVar via E-utilities (esearch, esummary, efetch) or FTP
• Understanding review status (star ratings) and conflicting interpretations
• Annotating variant call sets with clinical significance; see references/data_formats.md for VCF/XML/tab formats

Quick Start

The skill provides:

1. Project modules in src/tools/database/ncbi/: ncbi_clinvar.py (atomic E-utilities, term builder, FTP), ncbi_operations.py (query/download operations); ClinVar download functions re-exported via package.
2. References: references/api_reference.md, references/clinical_significance.md, references/data_formats.md

Agent Tools (Download Only)

Tool name	Arguments	Purpose
download_ncbi_clinvar_variants	term, out_path, retmax (optional, default 20)	Search ClinVar variants by term and save results to JSON

Also available as general NCBI tools (not ClinVar-specific but useful in ClinVar workflows):

Tool name	Arguments	Purpose
download_ncbi_sequence	ncbi_id, out_path, db (optional)	Download NCBI sequence by accession (FASTA)
download_ncbi_metadata	ncbi_id, out_path, db, rettype (optional)	Download NCBI metadata (GenBank/XML)
download_ncbi_blast	sequence, out_path, program, database, etc.	Submit BLAST search and download XML

Project Modules (Programmatic Use)

Capability	Function	Module	Purpose
Build search term	build_clinvar_term(gene, clinical_significance, condition, chr, variant_name, exclude_conflicting, raw_term)	ncbi_clinvar.py	Build E-utilities query string
High-level search	query_clinvar(term, retmax, retstart, retmode, api_key)	ncbi_clinvar.py	Search ClinVar, return esearch response text
Get summaries	get_clinvar_summary(variation_ids, retmode, api_key)	ncbi_clinvar.py	Get variant summaries by IDs
Full records	fetch_clinvar_records(variation_ids, rettype, retmode, api_key)	ncbi_clinvar.py	Fetch full XML/VCV records
Parse IDs	parse_esearch_ids(esearch_response_text)	ncbi_clinvar.py	Extract Variation IDs from esearch JSON
Parse count	parse_esearch_count(esearch_response_text)	ncbi_clinvar.py	Extract total count from esearch JSON
FTP URL	get_clinvar_ftp_url(key)	ncbi_clinvar.py	Get FTP URL by key (variant_summary, vcf_grch38, xml_latest, etc.)
FTP download	download_clinvar_ftp(url_or_key, out_dir, filename)	ncbi_clinvar.py	Download file from ClinVar FTP
Atomic esearch	clinvar_esearch(term, retmax, retstart, retmode, api_key, sort)	ncbi_clinvar.py	Raw esearch response text
Atomic esummary	clinvar_esummary(id_list, retmode, api_key)	ncbi_clinvar.py	Raw esummary response text
Atomic efetch	clinvar_efetch(id_list, rettype, retmode, api_key)	ncbi_clinvar.py	Raw efetch response text
Query: esearch	query_ncbi_clinvar_esearch(term, retmax, retstart, retmode)	ncbi_operations.py	Returns rich JSON in memory
Query: esummary	query_ncbi_clinvar_esummary(id_list, retmode)	ncbi_operations.py	Returns rich JSON in memory
Query: efetch	query_ncbi_clinvar_efetch(id_list, rettype, retmode)	ncbi_operations.py	Returns rich JSON in memory
Query: variants	query_ncbi_clinvar_variants(term, retmax)	ncbi_operations.py	Compound: esearch → returns rich JSON
Download: esearch	download_ncbi_clinvar_esearch(term, out_path, retmax, retstart, retmode)	ncbi_operations.py	Save esearch results to file
Download: esummary	download_ncbi_clinvar_esummary(id_list, out_path, retmode)	ncbi_operations.py	Save esummary results to file
Download: efetch	download_ncbi_clinvar_efetch(id_list, out_path, rettype, retmode)	ncbi_operations.py	Save efetch results to file
Download: variants	download_ncbi_clinvar_variants(term, out_path, retmax)	ncbi_operations.py	Compound: esearch → save to file

Core Capabilities

1. Search ClinVar Variants (download)

from src.tools.database.ncbi import download_ncbi_clinvar_variants

# Simple gene search
result = download_ncbi_clinvar_variants("BRCA1[gene]", "output/clinvar_brca1.json", retmax=50)

# Pathogenic variants for a gene
result = download_ncbi_clinvar_variants(
    "BRCA1[gene] AND pathogenic[CLNSIG]",
    "output/clinvar_brca1_pathogenic.json",
    retmax=100,
)

2. Build Search Terms (programmatic)

from src.tools.database.ncbi.ncbi_clinvar import build_clinvar_term

# Build term with filters
term = build_clinvar_term(
    gene="BRCA1",
    clinical_significance="pathogenic",
    exclude_conflicting=True,
)
# → "BRCA1[gene] AND pathogenic[CLNSIG] NOT conflicting[RVSTAT]"

# Search by condition
term = build_clinvar_term(condition="breast cancer")
# → "breast cancer[disorder]"

3. Atomic E-utilities Workflow (programmatic)

from src.tools.database.ncbi.ncbi_clinvar import (
    build_clinvar_term, query_clinvar, parse_esearch_ids,
    get_clinvar_summary, fetch_clinvar_records,
)

# Step 1: Build term and search
term = build_clinvar_term(gene="BRCA1", clinical_significance="pathogenic")
esearch_result = query_clinvar(term, retmax=100)

# Step 2: Parse IDs
variation_ids = parse_esearch_ids(esearch_result)

# Step 3: Get summaries or full records
summaries = get_clinvar_summary(variation_ids)
records = fetch_clinvar_records(variation_ids, rettype="vcv")

4. Download Atomic Results

from src.tools.database.ncbi import (
    download_ncbi_clinvar_esearch,
    download_ncbi_clinvar_esummary,
    download_ncbi_clinvar_efetch,
)

# Save esearch results
download_ncbi_clinvar_esearch("BRCA1[gene]", "output/clinvar_esearch.json", retmax=50)

# Save summaries (need IDs from esearch first)
download_ncbi_clinvar_esummary(["12345", "67890"], "output/clinvar_esummary.json")

# Save full records
download_ncbi_clinvar_efetch(["12345", "67890"], "output/clinvar_efetch.xml")

5. FTP Bulk Downloads (programmatic)

from src.tools.database.ncbi.ncbi_clinvar import get_clinvar_ftp_url, download_clinvar_ftp

# Get FTP URL
url = get_clinvar_ftp_url("variant_summary")  # Or: vcf_grch37, vcf_grch38, xml_latest, var_citations, cross_references

# Download
download_clinvar_ftp("variant_summary", "output/clinvar_ftp/")
download_clinvar_ftp("vcf_grch38", "output/clinvar_ftp/")

Key Concepts

• Search fields: [gene], [CLNSIG], [disorder], [variant name], [chr], [RVSTAT] (e.g. exclude conflicts: NOT conflicting[RVSTAT])
• Variation ID (VCV): ClinVar variation accession; returned by esearch as UID and used in esummary/efetch
• rettype: vcv (variant-centric) or rcv (variant–condition pair) for efetch

Important Notes

• ClinVar data is not for direct clinical diagnosis; involve a genetics professional
• Prefer high review status (e.g. expert panel, practice guideline) when interpreting classifications
• Use exclude_conflicting=True in build_clinvar_term to filter out conflicting interpretations
• Rate limits: 3 req/s without API key, 10 with key; the module applies delays automatically

Reference Documentation

• references/api_reference.md – E-utilities (esearch, esummary, efetch, elink), parameters, rate limits, Biopython example
• references/clinical_significance.md – Germline/somatic classifications, ACMG/AMP terms, review status, conflict resolution
• references/data_formats.md – FTP layout, XML (VCV/RCV), VCF, tab-delimited files, processing examples