rs76956014

Positions:

chr10-18527636-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_201596.3(CACNB2):c.993G>A(p.Ser331=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,613,820 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0082 ( 12 hom., cov: 32)

Exomes 𝑓: 0.010 ( 106 hom. )

Consequence

CACNB2
NM_201596.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0970

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 Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 10-18527636-G-A is Benign according to our data. Variant chr10-18527636-G-A is described in ClinVar as [Benign]. Clinvar id is 242263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-18527636-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.097 with no splicing effect.

BS2

High AC in GnomAd4 at 1245 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CACNB2	NM_201596.3 linkuse as main transcript	c.993G>A	p.Ser331=	synonymous_variant	10/14	ENST00000324631.13
CACNB2	NM_201590.3 linkuse as main transcript	c.831G>A	p.Ser277=	synonymous_variant	9/13	ENST00000377329.10
LOC124902386	XR_007062076.1 linkuse as main transcript	n.84-8806C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	UniProt
CACNB2	ENST00000324631.13 linkuse as main transcript	c.993G>A	p.Ser331=	synonymous_variant	10/14	1	NM_201596.3	Q08289-1
CACNB2	ENST00000377329.10 linkuse as main transcript	c.831G>A	p.Ser277=	synonymous_variant	9/13	1	NM_201590.3	Q08289-3
	ENST00000425669.1 linkuse as main transcript	n.482+11558C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.00818

AC:

1244

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00544

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.00603

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.000851

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00725

AC:

1821

AN:

251300

Hom.:

AF XY:

0.00705

AC XY:

957

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.00523

Gnomad AMR exome

AF:

0.00434

Gnomad ASJ exome

AF:

0.00963

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00287

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.0116

Gnomad OTH exome

AF:

0.00815

GnomAD4 exome

AF:

0.0102

AC:

14909

AN:

1461692

Hom.:

106

Cov.:

AF XY:

0.00998

AC XY:

7254

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.00493

Gnomad4 AMR exome

AF:

0.00452

Gnomad4 ASJ exome

AF:

0.00972

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00294

Gnomad4 FIN exome

AF:

0.00180

Gnomad4 NFE exome

AF:

0.0120

Gnomad4 OTH exome

AF:

0.00795

GnomAD4 genome

AF:

0.00818

AC:

1245

AN:

152128

Hom.:

Cov.:

AF XY:

0.00756

AC XY:

562

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00549

Gnomad4 AMR

AF:

0.00602

Gnomad4 ASJ

AF:

0.0135

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00291

Gnomad4 FIN

AF:

0.000851

Gnomad4 NFE

AF:

0.0119

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.0109

Hom.:

Bravo

AF:

0.00842

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0105

EpiControl

AF:

0.0116

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	CACNB2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2016	Variant summary: The CACNB2 c.831G>A (p.Ser277Ser) variant causes a synonymous change involving a non-conserved nucleotide. 5/5 splice prediction tools predict no significant impact on normal splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 884/121214 (1/137, 9 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic CACNB2 variant of 1/100000 (0.00001), suggesting this variant is likely a benign polymorphism. A reputable clinical laboratory cites the variant as "benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign. -

Brugada syndrome 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2015

This alteration is classified as 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

BayesDel_noAF

Benign

-0.36

CADD

Benign

8.2

DANN

Benign

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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