10-18539262-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_201596.3(CACNB2):c.1521C>T(p.Ser507Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00769 in 1,613,944 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S507S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0055 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0079 ( 57 hom. )

Consequence

CACNB2
NM_201596.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.383

Publications

4 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: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_addAF=-0.568183).

BP6

Variant 10-18539262-C-T is Benign according to our data. Variant chr10-18539262-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 242261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.383 with no splicing effect.

BS2

High AC in GnomAd4 at 829 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3 link	c.1521C>T	p.Ser507Ser	synonymous_variant	Exon 14 of 14	ENST00000324631.13	NP_963890.2	Q08289-1
CACNB2	NM_201590.3 link	c.1359C>T	p.Ser453Ser	synonymous_variant	Exon 13 of 13	ENST00000377329.10	NP_963884.2	Q08289-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13 link	c.1521C>T	p.Ser507Ser	synonymous_variant	Exon 14 of 14	1	NM_201596.3	ENSP00000320025.8		Q08289-1
CACNB2	ENST00000377329.10 link	c.1359C>T	p.Ser453Ser	synonymous_variant	Exon 13 of 13	1	NM_201590.3	ENSP00000366546.4		Q08289-3

Frequencies

GnomAD3 genomes

AF:

0.00546

AC:

830

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00336

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00460

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00841

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00475

AC:

1194

AN:

251322

AF XY:

0.00470

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.00402

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.000816

Gnomad FIN exome

AF:

0.00194

Gnomad NFE exome

AF:

0.00762

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00792

AC:

11575

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00781

AC XY:

5680

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00311

AC:

104

AN:

33480

American (AMR)

AF:

0.00423

AC:

189

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00107

AC:

AN:

26136

East Asian (EAS)

AF:

0.000605

AC:

AN:

39690

South Asian (SAS)

AF:

0.00239

AC:

206

AN:

86252

European-Finnish (FIN)

AF:

0.00174

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00944

AC:

10501

AN:

1111984

Other (OTH)

AF:

0.00695

AC:

420

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

650

1300

1949

2599

3249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

414

828

1242

1656

2070

<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:

0.00545

AC:

829

AN:

152098

Hom.:

Cov.:

AF XY:

0.00496

AC XY:

369

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00333

AC:

138

AN:

41492

American (AMR)

AF:

0.00459

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00116

AC:

AN:

5160

South Asian (SAS)

AF:

0.00395

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00841

AC:

572

AN:

68006

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00408

Hom.:

Bravo

AF:

0.00575

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.00826

AC:

ExAC

AF:

0.00446

AC:

542

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNB2: BP4, BP7, BS2; ENSG00000240291: BS2 -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Brugada syndrome 4

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 27, 2015

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

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

7.5

(source)

DANN

Benign

0.79

FATHMM_MKL

Benign

0.0089

PhyloP100

-0.38

GERP RS

-3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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