rs146333579

Description

Variant classified as Uncertain Significance - Favor Benign. The Ile161Val varia nt (CASQ2) has been identified in 3/7020 European American chromosomes from a br oad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS; dbSNP rs146333579). Computational analyses (biochemical amino acid prope rties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ile161Val variant may not impact the protein, though this information is not predictive en ough to rule out pathogenicity. Additional information is needed to fully assess the clinical significance of this variant.

In silico models in agreement (benign);Insufficient evidence;Subpopulation frequency in support of benign classification

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28404607)

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 161 of the CASQ2 protein (p.Ile161Val). This variant is present in population databases (rs146333579, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CASQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 44167). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.