rs150722502

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_201596.3(CACNB2):c.209G>A(p.Arg70His) variant causes a missense change. The variant allele was found at a frequency of 0.000973 in 1,568,760 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R70C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00099 ( 1 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.14

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:

CACNB2 (HGNC:):

CACNB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.045506954).

BP6

Variant 10-18150971-G-A is Benign according to our data. Variant chr10-18150971-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 190713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-18150971-G-A is described in Lovd as [Likely_benign]. Variant chr10-18150971-G-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 109 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB2	NM_201596.3 linkuse as main transcript	c.209G>A	p.Arg70His	missense_variant	2/14	ENST00000324631.13	NP_963890.2	Q08289-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13 linkuse as main transcript	c.209G>A	p.Arg70His	missense_variant	2/14	1	NM_201596.3	ENSP00000320025.8		Q08289-1

Frequencies

GnomAD3 genomes

AF:

0.000756

AC:

109

AN:

144244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000203

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000579

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000594

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000773

AC:

194

AN:

251022

Hom.:

AF XY:

0.000833

AC XY:

113

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000832

Gnomad NFE exome

AF:

0.00143

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000995

AC:

1417

AN:

1424406

Hom.:

Cov.:

AF XY:

0.000991

AC XY:

703

AN XY:

709514

show subpopulations

Gnomad4 AFR exome

AF:

0.0000924

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.000197

Gnomad4 EAS exome

AF:

0.0000801

Gnomad4 SAS exome

AF:

0.0000467

Gnomad4 FIN exome

AF:

0.000701

Gnomad4 NFE exome

AF:

0.00121

Gnomad4 OTH exome

AF:

0.000821

GnomAD4 genome

AF:

0.000755

AC:

109

AN:

144354

Hom.:

Cov.:

AF XY:

0.000661

AC XY:

AN XY:

69556

show subpopulations

Gnomad4 AFR

AF:

0.000203

Gnomad4 AMR

AF:

0.000578

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000594

Gnomad4 NFE

AF:

0.00132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.000737

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000881

AC:

107

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28255936, 23861362) -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

- -

CACNB2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.;T;.;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;.;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.046

T;T;T;T;T;T

MetaSVM

Uncertain

0.31

MutationAssessor

Benign

1.0

L;L;.;.;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.5

D;N;N;.;.;N

REVEL

Uncertain

0.46

Sift

Uncertain

0.0010

D;D;D;.;.;D

Sift4G

Benign

0.095

T;T;D;.;.;T

Polyphen

0.98

D;P;D;.;.;D

Vest4

0.93

MVP

0.89

MPC

0.61

ClinPred

0.086

GERP RS

5.9

Varity_R

0.22

gMVP

0.28

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