ClinVar

Description

Variant summary: CYBA c.203+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5' splicing donor site. Three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00024 in 244146 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CYBA causing Chronic Granulomatous Disease (0.00024 vs 0.00061), allowing no conclusion about variant significance. c.203+5G>A has been reported in the literature in one individual affected with Chronic Granulomatous Disease (Sacco_2019). The report does not provide unequivocal conclusions about association of the variant with Chronic Granulomatous Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31813112). ClinVar contains an entry for this variant (Variation ID: 534660). Based on the evidence outlined above, the variant was classified as uncertain significance.