ClinVar

Description

A variant of uncertain significance has been identified in the SCN9A gene. The c.2187 T>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.2187 T>G variant is observed in 3/4574 (0.1%) alleles from individuals of African background, (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.2187 T>G creates a cryptic donor site which may supplant the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.2187 T>G does not effect splicing, it will result in a I729M missense variant. The I729M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals.In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.