NM_201596.3:c.1591C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_201596.3(CACNB2):c.1591C>G(p.Arg531Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R531C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.96

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

Brugada syndrome 4
Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Laboratory for Molecular Medicine
Brugada syndrome 1
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
short QT syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CACNB2 links:

ENSG00000240291 (HGNC:58168):

ENSG00000240291 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20125988).

BP6

Variant 10-18539332-C-G is Benign according to our data. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294.

BS2

High AC in GnomAdExome4 at 7 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3 link	c.1591C>G	p.Arg531Gly	missense_variant	Exon 14 of 14	ENST00000324631.13	NP_963890.2	Q08289-1
CACNB2	NM_201590.3 link	c.1429C>G	p.Arg477Gly	missense_variant	Exon 13 of 13	ENST00000377329.10	NP_963884.2	Q08289-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13 link	c.1591C>G	p.Arg531Gly	missense_variant	Exon 14 of 14	1	NM_201596.3	ENSP00000320025.8		Q08289-1
CACNB2	ENST00000377329.10 link	c.1429C>G	p.Arg477Gly	missense_variant	Exon 13 of 13	1	NM_201590.3	ENSP00000366546.4		Q08289-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251354

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111994

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.000196

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brugada syndrome 4

Uncertain:1

Aug 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. 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. ClinVar contains an entry for this variant (Variation ID: 660294). This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 477 of the CACNB2 protein (p.Arg477Gly). -

Cardiovascular phenotype

Benign:1

Oct 03, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.14

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

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

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

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

M_CAP

Benign

0.028

MetaRNN

Benign

0.20

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

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.2

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

PhyloP100

3.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.1

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

REVEL

Uncertain

0.32

Sift

Benign

0.15

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

Sift4G

Benign

0.18

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

Polyphen

0.99

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

Vest4

0.68

MutPred

0.18

Loss of MoRF binding (P = 0.0075);.;.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.88

MPC

0.77

ClinPred

0.25

GERP RS

4.9

Varity_R

0.22

gMVP

0.48

Mutation Taster

=55/45

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over