rs142639223

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_201596.3(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 Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 3.08

Variant links:

Genes affected

CACNB2 (HGNC:1402): (calcium voltage-gated channel auxiliary subunit beta 2) This gene encodes a subunit of a voltage-dependent calcium channel protein that is a member of the voltage-gated calcium channel superfamily. The gene product was originally identified as an antigen target in Lambert-Eaton myasthenic syndrome, an autoimmune disorder. Mutations in this gene are associated with Brugada syndrome. Alternatively spliced variants encoding different isoforms have been described. [provided by RefSeq, Feb 2013]

CACNB2 links:

ENSG00000240291 (HGNC:):

ENSG00000240291 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015302777).

BP6

Variant 10-18539443-G-A is Benign according to our data. Variant chr10-18539443-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190717.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}.

BS2

High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB2	NM_201596.3 linkuse as main transcript	c.1702G>A	p.Val568Ile	missense_variant	14/14	ENST00000324631.13	NP_963890.2	Q08289-1
CACNB2	NM_201590.3 linkuse as main transcript	c.1540G>A	p.Val514Ile	missense_variant	13/13	ENST00000377329.10	NP_963884.2	Q08289-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13 linkuse as main transcript	c.1702G>A	p.Val568Ile	missense_variant	14/14	1	NM_201596.3	ENSP00000320025.8		Q08289-1
CACNB2	ENST00000377329.10 linkuse as main transcript	c.1540G>A	p.Val514Ile	missense_variant	13/13	1	NM_201590.3	ENSP00000366546.4		Q08289-3

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000243

AC:

AN:

251242

Hom.:

AF XY:

0.000236

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000291

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000268

AC:

392

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

177

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000308

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000237

AC:

AN:

152002

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000590

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000959

Alfa

AF:

0.000242

Hom.:

Bravo

AF:

0.000446

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Brugada syndrome 4

Uncertain:3

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	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	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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.061

T;.;T;.;.;.;T;T;.;.;.;T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.75

T;T;T;.;T;T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.015

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

N;.;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.33

N;N;N;.;.;N;.;.;N;N;N;.;N;.

REVEL

Benign

0.16

Sift

Benign

0.39

T;T;T;.;.;T;.;.;T;T;T;.;T;.

Sift4G

Benign

0.49

T;T;T;.;.;T;T;T;T;T;T;T;T;.

Polyphen

0.0010

B;B;P;.;.;B;.;.;.;B;B;.;.;.

Vest4

0.026

MVP

0.56

MPC

0.16

ClinPred

0.010

GERP RS

4.0

Varity_R

0.036

gMVP

0.046

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over