The PP2 and BP1 rules are gene-level rules, related to how much the gene is sensitive to missense variants
PP2 rule
PP2 should be applied in the case of “Missense variant in a gene with a low rate of benign missense mutations and for which missense mutation is a common mechanism of a disease”.
Franklin applies this rule in two cases:
Three times or more pathogenic missense variants than benign missense variants, and at least 8 pathogenic variants exist in the gene, supporting missense is a known mechanism of disease in the gene.
In the case of gnomAD missense O/E upper score is less than 0.35, which suggest this is intolerance to missense variants
BP1 rule
BP1 should be applied in the case of “Missense variant in a gene for which loss of function is the known mechanism of disease”.
We use a cautious approach when applying this rule, by requesting for zero reported missense pathogenic variants. Additionally to support this gene is well studied enough for applying this rule we require at least 30 known pathogenic Loss of Function (LOF) variants.
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