rs61733968

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_201596.3(CACNB2):c.1816C>G(p.Arg606Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0149 in 1,613,704 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 12 hom., cov: 30)

Exomes 𝑓: 0.015 ( 182 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 5.05

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:58168):

ENSG00000240291 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0092638135).

BP6

Variant 10-18539557-C-G is Benign according to our data. Variant chr10-18539557-C-G is described in ClinVar as [Benign]. Clinvar id is 191569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-18539557-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0112 (1702/151858) while in subpopulation NFE AF= 0.0177 (1206/67950). AF 95% confidence interval is 0.0169. There are 12 homozygotes in gnomad4. There are 855 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1702 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB2	NM_201596.3 link	c.1816C>G	p.Arg606Gly	missense_variant	14/14	ENST00000324631.13	NP_963890.2	Q08289-1
CACNB2	NM_201590.3 link	c.1654C>G	p.Arg552Gly	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 link	c.1816C>G	p.Arg606Gly	missense_variant	14/14	1	NM_201596.3	ENSP00000320025.8		Q08289-1
CACNB2	ENST00000377329.10 link	c.1654C>G	p.Arg552Gly	missense_variant	13/13	1	NM_201590.3	ENSP00000366546.4		Q08289-3

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1702

AN:

151742

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00320

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00230

Gnomad FIN

AF:

0.00681

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0177

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00911

AC:

2288

AN:

251274

Hom.:

AF XY:

0.00900

AC XY:

1222

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.00523

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00189

Gnomad FIN exome

AF:

0.00494

Gnomad NFE exome

AF:

0.0159

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.0153

AC:

22325

AN:

1461846

Hom.:

182

Cov.:

AF XY:

0.0148

AC XY:

10751

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00221

Gnomad4 AMR exome

AF:

0.00552

Gnomad4 ASJ exome

AF:

0.00279

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00188

Gnomad4 FIN exome

AF:

0.00532

Gnomad4 NFE exome

AF:

0.0186

Gnomad4 OTH exome

AF:

0.0133

GnomAD4 genome

AF:

0.0112

AC:

1702

AN:

151858

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

855

AN XY:

74192

show subpopulations

Gnomad4 AFR

AF:

0.00319

Gnomad4 AMR

AF:

0.0157

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00230

Gnomad4 FIN

AF:

0.00681

Gnomad4 NFE

AF:

0.0177

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00581

Hom.:

Bravo

AF:

0.0109

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0197

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0170

AC:

146

ExAC

AF:

0.00918

AC:

1114

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0148

EpiControl

AF:

0.0149

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Brugada syndrome 4

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	May 12, 2016	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2015

This alteration is classified as 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. -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy;C0039240:Supraventricular tachycardia;C0042514:Ventricular tachycardia;C0878544:Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Mar 15, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

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

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D;.;D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0093

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

MetaSVM

Uncertain

0.10

MutationAssessor

Uncertain

2.3

M;.;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.92

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

REVEL

Benign

0.28

Sift

Uncertain

0.0040

D;D;D;.;.;D;.;.;D;D;D;.;D;.

Sift4G

Uncertain

0.036

D;D;T;.;.;D;T;D;D;D;D;D;D;.

Polyphen

0.96

D;P;D;.;.;D;.;.;.;P;D;.;.;.

Vest4

0.40

MVP

0.88

MPC

0.59

ClinPred

0.013

GERP RS

5.9

Varity_R

0.093

gMVP

0.083

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