rs142639223
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The ENST00000324631.13(CACNB2):c.1702G>A(p.Val568Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V568L) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000324631.13 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNB2 | NM_201596.3 | c.1702G>A | p.Val568Ile | missense_variant | 14/14 | ENST00000324631.13 | NP_963890.2 | |
CACNB2 | NM_201590.3 | c.1540G>A | p.Val514Ile | missense_variant | 13/13 | ENST00000377329.10 | NP_963884.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNB2 | ENST00000324631.13 | c.1702G>A | p.Val568Ile | missense_variant | 14/14 | 1 | NM_201596.3 | ENSP00000320025 | ||
CACNB2 | ENST00000377329.10 | c.1540G>A | p.Val514Ile | missense_variant | 13/13 | 1 | NM_201590.3 | ENSP00000366546 | ||
ENST00000425669.1 | n.377-144C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes AF: 0.000237 AC: 36AN: 152002Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.000243 AC: 61AN: 251242Hom.: 0 AF XY: 0.000236 AC XY: 32AN XY: 135826
GnomAD4 exome AF: 0.000268 AC: 392AN: 1461858Hom.: 0 Cov.: 35 AF XY: 0.000243 AC XY: 177AN XY: 727230
GnomAD4 genome AF: 0.000237 AC: 36AN: 152002Hom.: 0 Cov.: 30 AF XY: 0.000175 AC XY: 13AN XY: 74224
ClinVar
Submissions by phenotype
Brugada syndrome 4 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 514 of the CACNB2 protein (p.Val514Ile). This variant is present in population databases (rs142639223, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Brugada syndrome (PMID: 25650408). ClinVar contains an entry for this variant (Variation ID: 190717). 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 with a negative predictive value of 80%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 04, 2021 | The CACNB2 c.1540G>A; p.Val514Ile variant (rs142639223), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 190717). This variant is found in the general population with an overall allele frequency of 0.02% (62/282604 alleles) in the Genome Aggregation Database. The valine at codon 514 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.16). Due to limited information, the clinical significance of the p.Val514Ile variant is uncertain at this time. Gene statement: Although variants in CACNB2 have been associated with Brugada syndrome 4 (MIM: 611876), the evidence supporting this association is limited (Hosseini 2018). Hosseini et al. Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome Circulation, 2018 Sep 18;138(12):1195-1205. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 15, 2021 | ACMG classification criteria: BP4 supporting - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 24, 2024 | Identified in patients with Brugada syndrome in published literature (PMID: 25650408, 34546463); In silico analysis indicates that this missense variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868); This variant is associated with the following publications: (PMID: 25650408, 34546463) - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 27, 2023 | Variant summary: CACNB2 c.1540G>A (p.Val514Ile) 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 0.00024 in 251242 control chromosomes (gnomAD). The observed variant frequency is approximately 78-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. c.1540G>A has been reported in the literature in an individual affected with Brugada Syndrome, without strong evidence for causality (Le Scouarnec_2015). Therefore, this report does not provide unequivocal conclusions about association of the variant with Brugada Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=4) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Mar 14, 2017 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 08, 2019 | 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