A common use case for the VEP is as a first step towards identifying the causal genetic variant of a rare phenotype from whole genome/exome sequencing. The VEP tells you which genes are hit, what effects they have on them, and you have to begin the long laborious process of filtering those down. Things you might consider include allele frequency, association with genes known to be involved in rare disease and whether both genes in a diploid organism are affected. Rather than faffing about doing this manually, you can use the G2P (genotype to phenotype) plugin instead, which was recently published as a preprint.

To develop the G2P plugin, Ensembl worked with colleagues at DECIPHER, who specialise in the identification of variants leading to rare disease. The G2P plugin makes use of a list of genes, created and updated by the team at DECIPHER, which includes all genes that are already known to be involved in rare disease. The list also includes the inheritance method (biallelic or monoallelic) of the disease phenotype.

The G2P plugin acts a filter. Its first filter finds only variants that affect genes on the list. Its second filter looks at variant consequences, identifying only variants which have a missense or loss of function effect on the genes on the list. The next step checks the allele frequencies of the variant in 1000 Genomes, gnomAD and ExAC (we do not expect to see high frequencies for rare disease causing variants) – the cut-off is determined by the inheritance method of the gene hit. Finally, the plugin checks the inheritance method: if this is monoallelic, we only need one copy of the gene to contain a variant that passes the filters, but if it’s biallelic we need evidence that both copies of the gene are affected (to do this it needs phased genotypes in the VCF). It then generates an easy to read report for you, telling you which variants are likely to be phenotype causing.

The plugin is easy to use alongside the VEP script, but you need to have a G2P list downloaded. As well as the list available from DECIPHER, you can also use data from PanelApp, or you can make your own.