rs1060499847

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_201596.3(CACNB2):c.1873C>T(p.Arg625Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,444 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R625H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.13

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB2	NM_201596.3 linkuse as main transcript	c.1873C>T	p.Arg625Cys	missense_variant	14/14	ENST00000324631.13
CACNB2	NM_201590.3 linkuse as main transcript	c.1711C>T	p.Arg571Cys	missense_variant	13/13	ENST00000377329.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	UniProt
CACNB2	ENST00000324631.13 linkuse as main transcript	c.1873C>T	p.Arg625Cys	missense_variant	14/14	1	NM_201596.3	Q08289-1
CACNB2	ENST00000377329.10 linkuse as main transcript	c.1711C>T	p.Arg571Cys	missense_variant	13/13	1	NM_201590.3	Q08289-3
	ENST00000425669.1 linkuse as main transcript	n.377-315G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

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

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251078

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461662

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151782

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74070

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 12, 2016

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: Reported in 1 proband with early repolarization syndrome -

Brugada syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2023

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. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 571 of the CACNB2 protein (p.Arg571Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of CACNB2-related conditions (PMID: 20817017). ClinVar contains an entry for this variant (Variation ID: 402475). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2023

The p.R571C variant (also known as c.1711C>T), located in coding exon 13 of the CACNB2 gene, results from a C to T substitution at nucleotide position 1711. The arginine at codon 571 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.28

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.34

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

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.088

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

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

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.59

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

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.3

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.3

N;N;D;.;.;N;.;.;N;N;N;.;N;N

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.60

MutPred

0.46

Loss of MoRF binding (P = 0.0236);.;.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.93

MPC

0.84

ClinPred

0.81

GERP RS

2.6

Varity_R

0.25

gMVP

0.25

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