GeneBe

Quick Start

Annotating a VCF File

The primary use case for GeneBe Hub is using its annotations to annotate a VCF file. Let’s assume you already have a VCF file containing a single Whole Exome Sequencing sample, based on the GRCh38 (hg38) reference genome, with variants normalized and represented as single alleles.

Prerequisites

Annotation

Start by logging into GeneBe. Run:

java -jar GeneBeClient.jar login

Next, choose the databases you want to use. For this example, we will use the GnomAD4 Exomes database to retrieve variant frequencies in the healthy population:

# This will download the database to your local computer
java -jar GeneBeClient.jar annotation pull

If using GnomAD, it’s good practice to check the depth of coverage to assess the reliability of the frequencies. Use the GnomAD depth database:

java -jar GeneBeClient.jar annotation pull --id @genebe/gnomad-exomes-depth:0.0.1-4.1.0

Finally, let’s annotate the variants using the current version of ClinVar:

java -jar GeneBeClient.jar annotation pull --id @genebe/clinvar:0.0.1-20250115

Now, let’s annotate your VCF file, we will also use CCRS anntations. Assuming your input file is named input.vcf.gz and the output should be written to output.vcf.gz and in annotated.tsv:

java -jar GeneBeClient.jar vcf annotate --input-vcf sample.vcf \
    --annotations @genebe/ccrs_hg38:0.0.1 @genebe/clinvar:0.0.1-20250115 @genebe/gnomad-exomes-depth:0.0.1-4.1.0 \
    --output-vcf /tmp/output.vcf.gz \
    --output-tsv /tmp/output.tsv

IMPORTANT NOTE: When you run vcf annotate this way, GeneBeClient does send variants to a server. It's because by default remote annotation named @genebe/base, that includes ACMG, consequences, GnomAD, ClinVar and more "basic" annotations is turned on. You can turn this behaviour off with --omit-base-annotation true.