rs144182966
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_201596.3(CACNB2):c.1776C>A(p.Asp592Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 1,613,940 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. D592D) has been classified as Likely benign.
Frequency
Consequence
NM_201596.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNB2 | NM_201596.3 | c.1776C>A | p.Asp592Glu | missense_variant | 14/14 | ENST00000324631.13 | |
CACNB2 | NM_201590.3 | c.1614C>A | p.Asp538Glu | missense_variant | 13/13 | ENST00000377329.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNB2 | ENST00000324631.13 | c.1776C>A | p.Asp592Glu | missense_variant | 14/14 | 1 | NM_201596.3 | ||
CACNB2 | ENST00000377329.10 | c.1614C>A | p.Asp538Glu | missense_variant | 13/13 | 1 | NM_201590.3 | ||
ENST00000425669.1 | n.377-218G>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000362 AC: 55AN: 151968Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.000438 AC: 110AN: 251314Hom.: 0 AF XY: 0.000501 AC XY: 68AN XY: 135828
GnomAD4 exome AF: 0.000447 AC: 653AN: 1461854Hom.: 3 Cov.: 35 AF XY: 0.000492 AC XY: 358AN XY: 727226
GnomAD4 genome ? AF: 0.000362 AC: 55AN: 152086Hom.: 0 Cov.: 30 AF XY: 0.000269 AC XY: 20AN XY: 74354
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 13, 2023 | Variant summary: CACNB2 c.1614C>A (p.Asp538Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 251314 control chromosomes. The observed variant frequency is approximately 140 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNB2 causing Brugada Syndrome phenotype (3.1e-06), strongly suggesting that the variant is benign. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=3, VUS n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 16, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency; Multiple papers classify as VUS; ClinVar: 1 LB, 2 VUS - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 11, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not provided Benign:2
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | Low GERP score may suggest that this variant may belong in a lower pathogenicity class - |
Brugada syndrome 4 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 10, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 09, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at