10-18527610-G-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_201596.3(CACNB2):c.967G>A(p.Ala323Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,613,590 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A323S) has been classified as Uncertain significance.
Frequency
Consequence
NM_201596.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNB2 | NM_201596.3 | c.967G>A | p.Ala323Thr | missense_variant | 10/14 | ENST00000324631.13 | |
CACNB2 | NM_201590.3 | c.805G>A | p.Ala269Thr | missense_variant | 9/13 | ENST00000377329.10 | |
LOC124902386 | XR_007062076.1 | n.84-8780C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNB2 | ENST00000324631.13 | c.967G>A | p.Ala323Thr | missense_variant | 10/14 | 1 | NM_201596.3 | ||
CACNB2 | ENST00000377329.10 | c.805G>A | p.Ala269Thr | missense_variant | 9/13 | 1 | NM_201590.3 | ||
ENST00000425669.1 | n.482+11584C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes AF: 0.000276 AC: 42AN: 152088Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000103 AC: 26AN: 251284Hom.: 1 AF XY: 0.0000810 AC XY: 11AN XY: 135804
GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461384Hom.: 1 Cov.: 30 AF XY: 0.0000248 AC XY: 18AN XY: 727054
GnomAD4 genome AF: 0.000276 AC: 42AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32AN XY: 74410
ClinVar
Submissions by phenotype
Brugada syndrome 4 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Nov 18, 2019 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP1. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 269 of the CACNB2 protein (p.Ala269Thr). This variant is present in population databases (rs561197163, gnomAD 0.06%), 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 CACNB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 537373). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 08, 2021 | The p.A269T variant (also known as c.805G>A), located in coding exon 9 of the CACNB2 gene, results from a G to A substitution at nucleotide position 805. The alanine at codon 269 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 08, 2020 | Variant summary: CACNB2 c.805G>A (p.Ala269Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251284 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 33-fold 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. To our knowledge, no occurrence of c.805G>A in individuals affected with Brugada Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at