10-18536187-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_201596.3(CACNB2):c.1293G>C(p.Gln431His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000432 in 1,387,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Q431Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.35

Publications

2 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: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.808

BS2

High AC in GnomAdExome4 at 6 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3 link	c.1293G>C	p.Gln431His	missense_variant	Exon 12 of 14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3 link	c.1131G>C	p.Gln377His	missense_variant	Exon 11 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.1293G>C	p.Gln431His	missense_variant	Exon 12 of 14	1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10 link	c.1131G>C	p.Gln377His	missense_variant	Exon 11 of 13	1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251386

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

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:

0.00000432

AC:

AN:

1387374

Hom.:

Cov.:

AF XY:

0.00000433

AC XY:

AN XY:

692064

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30950

American (AMR)

AF:

0.000139

AC:

AN:

43190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24544

East Asian (EAS)

AF:

0.00

AC:

AN:

35288

South Asian (SAS)

AF:

0.00

AC:

AN:

85096

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5494

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1056028

Other (OTH)

AF:

0.00

AC:

AN:

56292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brugada syndrome 4

Uncertain:1

Sep 27, 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 expected to disrupt CACNB2 protein function. ClinVar contains an entry for this variant (Variation ID: 1026738). This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. This variant is present in population databases (rs148414498, gnomAD 0.01%). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 377 of the CACNB2 protein (p.Gln377His).

Cardiovascular phenotype

Uncertain:1

Mar 09, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Q377H variant (also known as c.1131G>C), located in coding exon 11 of the CACNB2 gene, results from a G to C substitution at nucleotide position 1131. The glutamine at codon 377 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

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

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

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

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.81

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

3.2

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

PhyloP100

2.3

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.7

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

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Vest4

0.84

ClinPred

0.96

GERP RS

3.8

Varity_R

0.82

gMVP

0.73

Mutation Taster

=23/77

disease causing

(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