/bio-copy-number-cnv-annotation

name: bio-copy-number-cnv-annotation
description: Annotate CNVs with genes, pathways, and clinical significance. Use when interpreting CNV calls or identifying affected genes from copy number analysis.
tool_type: mixed
primary_tool: bedtools

Version Compatibility

Reference examples tested with: bedtools 2.31+, pandas 2.2+, pybedtools 0.9+, pysam 0.22+

Before using code patterns, verify installed versions match. If versions differ:

• Python: `pip show <package>` then `help(module.function)` to check signatures
• R: `packageVersion('<pkg>')` then `?function_name` to verify parameters
• CLI: `<tool> --version` then `<tool> --help` to confirm flags

If code throws ImportError, AttributeError, or TypeError, introspect the installed package and adapt the example to match the actual API rather than retrying.

CNV Annotation

**"Annotate my CNV calls with gene names"** → Overlap CNV segments with gene annotations, clinical databases, and pathway information to identify affected genes and assess clinical significance.

• CLI: `bedtools intersect -a cnvs.bed -b genes.bed`
• Python: `pybedtools.BedTool().intersect()`

Annotate with Gene Names (bedtools)

# Convert CNV segments to BED
awk 'NR>1 {print $1"\t"$2"\t"$3"\t"$5"\t"$6}' sample.cns > sample.cnv.bed

# Intersect with gene annotations
bedtools intersect -a sample.cnv.bed -b genes.bed -wa -wb > cnv_genes.txt

# Get genes overlapping CNVs
bedtools intersect -a genes.bed -b sample.cnv.bed -u > affected_genes.bed

CNVkit Gene Annotation

# Annotate during analysis
cnvkit.py batch tumor.bam --normal normal.bam \
    --targets targets.bed \
    --annotate refFlat.txt \
    --fasta reference.fa \
    -o results/

# Genes are included in output CNS file

Python: Comprehensive Annotation

**Goal:** Annotate CNV segments with all overlapping genes using interval intersection.

**Approach:** Convert CNV segments and gene annotations to BedTool objects, intersect to find overlapping genes, and aggregate gene names per CNV segment.

import pandas as pd
import pybedtools as pbt

def annotate_cnvs(cns_file, gene_bed, output=None):
    '''Annotate CNV segments with overlapping genes.'''
    cns = pd.read_csv(cns_file, sep='\t')

    # Create BED from segments
    cns_bed = pbt.BedTool.from_dataframe(
        cns[['chromosome', 'start', 'end', 'log2']].rename(
            columns={'chromosome': 'chrom'}))

    genes = pbt.BedTool(gene_bed)

    # Intersect
    intersect = cns_bed.intersect(genes, wa=True, wb=True)

    # Parse results
    results = []
    for interval in intersect:
        results.append({
            'chrom': interval[0],
            'start': int(interval[1]),
            'end': int(interval[2]),
            'log2': float(interval[3]),
            'gene_chrom': interval[4],
            'gene_start': int(interval[5]),
            'gene_end': int(interval[6]),
            'gene_name': interval[7] if len(interval) > 7 else 'NA'
        })

    df = pd.DataFrame(results)

    # Aggregate genes per CNV
    cnv_genes = df.groupby(['chrom', 'start', 'end', 'log2'])['gene_name'].apply(
        lambda x: ','.join(sorted(set(x)))).reset_index()

    if output:
        cnv_genes.to_csv(output, sep='\t', index=False)

    return cnv_genes

Annotate with Cancer Gene Census

**Goal:** Flag known cancer-associated genes within CNV regions.

**Approach:** Load the COSMIC Cancer Gene Census, cross-reference with genes overlapping CNVs, and tag matching genes.

import pandas as pd

def annotate_cancer_genes(cnv_genes, cgc_file):
    '''Flag cancer-associated genes in CNVs.'''
    cgc = pd.read_csv(cgc_file, sep='\t')
    cancer_genes = set(cgc['Gene Symbol'].tolist())

    def check_cancer_genes(genes):
        if pd.isna(genes):
            return ''
        gene_list = genes.split(',')
        cancer = [g for g in gene_list if g in cancer_genes]
        return ','.join(cancer)

    cnv_genes['cancer_genes'] = cnv_genes['gene_name'].apply(check_cancer_genes)
    cnv_genes['n_cancer_genes'] = cnv_genes['cancer_genes'].apply(
        lambda x: len(x.split(',')) if x else 0)

    return cnv_genes

Annotate with ACMG/ClinVar

**Goal:** Identify pathogenic ClinVar variants within CNV regions for clinical interpretation.

**Approach:** Query the ClinVar VCF for each CNV region using pysam, collect pathogenic variants and their associated genes.

def annotate_clinvar_cnvs(cnv_bed, clinvar_vcf):
    '''Annotate CNVs with ClinVar variants.'''
    import pysam

    cnv = pd.read_csv(cnv_bed, sep='\t', header=None,
        names=['chrom', 'start', 'end', 'log2'])

    vcf = pysam.VariantFile(clinvar_vcf)

    results = []
    for _, row in cnv.iterrows():
        chrom = row['chrom'].replace('chr', '')
        pathogenic = []

        for rec in vcf.fetch(chrom, row['start'], row['end']):
            clnsig = rec.info.get('CLNSIG', [''])[0]
            if 'pathogenic' in clnsig.lower():
                gene = rec.info.get('GENEINFO', 'NA').split(':')[0]
                pathogenic.append(gene)

        results.append({
            'chrom': row['chrom'],
            'start': row['start'],
            'end': row['end'],
            'log2': row['log2'],
            'clinvar_pathogenic': ','.join(set(pathogenic))
        })

    return pd.DataFrame(results)

GISTIC2 for Recurrent CNVs

# Export segments for GISTIC
cnvkit.py export seg *.cns -o cohort.seg

# Run GISTIC2
gistic2 \
    -b results/ \
    -seg cohort.seg \
    -refgene hg38.refgene.mat \
    -genegistic 1 \
    -smallmem 1 \
    -broad 1 \
    -brlen 0.5 \
    -conf 0.90 \
    -armpeel 1 \
    -savegene 1

# Output: significant regions with genes

AnnotSV for Comprehensive Annotation

# Export CNVs to VCF
cnvkit.py export vcf sample.cns -o sample.cnv.vcf

# Run AnnotSV
AnnotSV \
    -SVinputFile sample.cnv.vcf \
    -genomeBuild GRCh38 \
    -outputFile sample_annotated \
    -SVminSize 1000