10-18506518-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_201596.3(CACNB2):c.641G>C(p.Ser214Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00106 in 1,611,704 control chromosomes in the GnomAD database, including 6 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. S214N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 6 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:8

Conservation

PhyloP100: 7.03

Publications

15 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01582411).

BP6

Variant 10-18506518-G-C is Benign according to our data. Variant chr10-18506518-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161211.

BS2

High AC in GnomAd4 at 133 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3 link	c.641G>C	p.Ser214Thr	missense_variant	Exon 6 of 14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3 link	c.479G>C	p.Ser160Thr	missense_variant	Exon 5 of 13	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13 link	c.641G>C	p.Ser214Thr	missense_variant	Exon 6 of 14	1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10 link	c.479G>C	p.Ser160Thr	missense_variant	Exon 5 of 13	1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

133

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00100

AC:

251

AN:

250608

AF XY:

0.00116

show subpopulations

Gnomad AFR exome

AF:

0.000310

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00146

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.00108

AC:

1574

AN:

1459376

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

793

AN XY:

726198

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33424

American (AMR)

AF:

0.000671

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.00114

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.000543

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00434

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00118

AC:

1315

AN:

1109878

Other (OTH)

AF:

0.00104

AC:

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

132

197

263

329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.000873

AC:

133

AN:

152328

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41586

American (AMR)

AF:

0.00163

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00249

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00110

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000986

Hom.:

Bravo

AF:

0.000756

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000988

AC:

120

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00153

EpiControl

AF:

0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Jun 10, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the lack of case data, the location and presence in general population (reviewed below) we consider this a variant of uncertain significance, probably benign. The variant is novel. This variant is in an alternative transcript where no disease-causing variants have been reported to date, according to HGMD. In total the variant has been seen in 18 of 8,254 individuals from publicly available general population datasets. The variant was reported online in 10 of 4300 Caucasian individuals and 1 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of June 10th, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that cardiomyopathy variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). It is listed in dbSNP (rs149253719), with data from NHLBI ESP, 1000 genomes, and ClinSeq. It looks like it was seen in 1 of 662 individuals in ClinSeq. It was observed in 6 of 1089 individuals in phase 1 of 1000 genomes including 2 of 85 American Caucasians, 2 of 93 Finnish, and 2 of 98 Italians. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only 1 proband in HGMD, ExAC: 0.1% (23/16008) South Asian chromosomes -

Oct 26, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CACNB2 c.479G>C (p.Ser160Thr) results in a conservative amino acid change located in the SH3 domain (IPR001452) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.005 in 250611 control chromosomes, predominantly at a frequency of 0.0015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 480 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.479G>C has been reported in the literature in individuals affected with early repolarization syndrome, Brugada Syndrome and Sudden cardiac death (Burashnikov_2010, Crotti_2012, Christiansen_2016). These reports do 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. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x), likely benign (4x) and benign (1x). Based on the evidence outlined above, the variant was classified as likely benign. -

Brugada syndrome 4

Uncertain:1Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 25, 2019

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Sep 23, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25637381, 20817017, 24055113, 23861362, 27650965) -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNB2: BP4, BS1, BS2 -

Early repolarization associated with ventricular fibrillation

Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Long QT syndrome

Uncertain:1

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Criteria: BS1, PP3 -

Brugada syndrome

Benign:1

Feb 27, 2018

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 09, 2018

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

0.089

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

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

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.80

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

M_CAP

Benign

0.059

MetaRNN

Benign

0.016

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

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

0.69

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

PhyloP100

7.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.0

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

REVEL

Uncertain

0.36

Sift

Uncertain

0.010

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

Sift4G

Benign

0.14

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

Polyphen

0.0010

B;B;.;.;B;.;.;B;B;B;.;.;.

Vest4

0.39

MVP

0.84

MPC

0.29

ClinPred

0.025

GERP RS

5.9

Varity_R

0.34

gMVP

0.29

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over