ClinVar Miner

Submissions for variant NM_201596.3(CACNB2):c.427G>A (p.Glu143Lys)

gnomAD frequency: 0.00004  dbSNP: rs368719191
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000171624 SCV000055192 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV001221411 SCV001393455 uncertain significance Brugada syndrome 4 2023-08-01 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNB2 protein function. ClinVar contains an entry for this variant (Variation ID: 191432). This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. This variant is present in population databases (rs368719191, gnomAD 0.04%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 89 of the CACNB2 protein (p.Glu89Lys).
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000171624 SCV001554338 uncertain significance not provided no assertion criteria provided clinical testing The CACNB2 p.Glu88Lys variant was not identified in the literature but was identified in dbSNP (ID: rs368719191), Cosmic, LOVD 3.0 and ClinVar (classified as a VUS by Biesecker Lab/Human Development Section, National Institutes of Health and Illumina for Brugada Syndrome). The variant was identified in control databases in 11 of 282722 chromosomes at a frequency of 0.000039 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 4 of 10368 chromosomes (freq: 0.000386), African in 1 of 24972 chromosomes (freq: 0.00004), European (non-Finnish) in 5 of 129064 chromosomes (freq: 0.000039), and South Asian in 1 of 30612 chromosomes (freq: 0.000033), but not in the Latino, East Asian, European (Finnish) or Other populations. The p.Glu88 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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