10-18539706-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_201596.3(CACNB2):c.1965T>G(p.Asp655Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,606,432 control chromosomes in the GnomAD database, including 22,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D655H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.14 ( 1727 hom., cov: 29)

Exomes 𝑓: 0.16 ( 21003 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.31

Publications

24 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018334389).

BP6

Variant 10-18539706-T-G is Benign according to our data. Variant chr10-18539706-T-G is described in ClinVar as Benign. ClinVar VariationId is 136649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201596.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNB2	NM_201596.3	MANE Select	c.1965T>G	p.Asp655Glu	missense	Exon 14 of 14	NP_963890.2
CACNB2	NM_201590.3	MANE Plus Clinical	c.1803T>G	p.Asp601Glu	missense	Exon 13 of 13	NP_963884.2
CACNB2	NM_201597.3		c.1893T>G	p.Asp631Glu	missense	Exon 14 of 14	NP_963891.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.1965T>G	p.Asp655Glu	missense	Exon 14 of 14	ENSP00000320025.8
CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.1803T>G	p.Asp601Glu	missense	Exon 13 of 13	ENSP00000366546.4
CACNB2	ENST00000352115.10	TSL:1	c.1893T>G	p.Asp631Glu	missense	Exon 14 of 14	ENSP00000344474.6

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

21739

AN:

150348

Hom.:

1726

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.157

Gnomad AMR

AF:

0.118

Gnomad ASJ

AF:

0.159

Gnomad EAS

AF:

0.00117

Gnomad SAS

AF:

0.0774

Gnomad FIN

AF:

0.203

Gnomad MID

AF:

0.223

Gnomad NFE

AF:

0.179

Gnomad OTH

AF:

0.156

GnomAD2 exomes

AF:

0.136

AC:

33157

AN:

244118

AF XY:

0.137

show subpopulations

Gnomad AFR exome

AF:

0.107

Gnomad AMR exome

AF:

0.0842

Gnomad ASJ exome

AF:

0.152

Gnomad EAS exome

AF:

0.000725

Gnomad FIN exome

AF:

0.195

Gnomad NFE exome

AF:

0.180

Gnomad OTH exome

AF:

0.153

GnomAD4 exome

AF:

0.163

AC:

237280

AN:

1456050

Hom.:

21003

Cov.:

AF XY:

0.162

AC XY:

117043

AN XY:

724412

show subpopulations

African (AFR)

AF:

0.106

AC:

3527

AN:

33154

American (AMR)

AF:

0.0893

AC:

3916

AN:

43848

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

4056

AN:

25850

East Asian (EAS)

AF:

0.000428

AC:

AN:

39686

South Asian (SAS)

AF:

0.0780

AC:

6666

AN:

85446

European-Finnish (FIN)

AF:

0.195

AC:

10322

AN:

52860

Middle Eastern (MID)

AF:

0.195

AC:

1114

AN:

5714

European-Non Finnish (NFE)

AF:

0.179

AC:

198468

AN:

1109422

Other (OTH)

AF:

0.153

AC:

9194

AN:

60070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

9752

19504

29255

39007

48759

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6730

13460

20190

26920

33650

<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:

0.145

AC:

21744

AN:

150382

Hom.:

1727

Cov.:

AF XY:

0.143

AC XY:

10486

AN XY:

73206

show subpopulations

African (AFR)

AF:

0.107

AC:

4392

AN:

40954

American (AMR)

AF:

0.118

AC:

1774

AN:

15084

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

552

AN:

3464

East Asian (EAS)

AF:

0.00118

AC:

AN:

5106

South Asian (SAS)

AF:

0.0766

AC:

362

AN:

4728

European-Finnish (FIN)

AF:

0.203

AC:

2016

AN:

9946

Middle Eastern (MID)

AF:

0.234

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.179

AC:

12110

AN:

67814

Other (OTH)

AF:

0.154

AC:

322

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

912

1824

2737

3649

4561

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<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:

0.156

Hom.:

3971

Bravo

AF:

0.139

TwinsUK

AF:

0.176

AC:

652

ALSPAC

AF:

0.180

AC:

695

ESP6500AA

AF:

0.110

AC:

485

ESP6500EA

AF:

0.173

AC:

1486

ExAC

AF:

0.137

AC:

16656

Asia WGS

AF:

0.0500

AC:

172

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Brugada syndrome 4 (1)

Cardiovascular phenotype (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

Eigen

Benign

0.0040

Eigen_PC

Benign

0.050

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.3

PhyloP100

1.3

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.82

REVEL

Uncertain

0.36

Sift

Uncertain

0.025

Sift4G

Uncertain

0.020

Polyphen

0.014

Vest4

0.19

MutPred

0.39

Gain of sheet (P = 0.0221)

MPC

0.19

ClinPred

0.0092

GERP RS

2.8

Varity_R

0.21

gMVP

0.19

Mutation Taster

=96/4

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over