New or cryptic splice site prediction. (A) Number of variants that generated alternative transcripts by new or cryptic splice site usage in our minigene splicing assays, categorized according to the original MES-based selection criteria (Vallée et al. 2016). (B) Number of variants with alternative transcript products correctly predicted by the updated SpliceAI-10k calculator (SAI-10k-calc). (C,D) Illustration of cryptic donor or acceptor activation prediction using the SpliceAI alternate scores integrated into the updated SAI-10k-calc algorithm. Variant location is indicated by the star symbol. SpliceAI alternate scores for cryptic (score ALT 1) and native (score ALT 0) splice sites suggested full usage of the cryptic sites, in agreement with SeqSplice results showing complete production of naturally occurring Δ5q22 and Δ8p3 alternative isoforms resulting from BRCA1 c.196A>T and c.442-2A>C, respectively.