NM_201596.3:c.1511C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_201596.3(CACNB2):c.1511C>T(p.Thr504Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,614,042 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T504T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0029 ( 11 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:12O:1

Conservation

PhyloP100: 0.904

Publications

16 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
cardiogenetic disease
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:

CACNB2-AS1 (HGNC:58168):

CACNB2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008203387).

BP6

Variant 10-18539252-C-T is Benign according to our data. Variant chr10-18539252-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161212.

BS2

High AC in GnomAd4 at 253 AD,Unknown gene.

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	UniProt
CACNB2	NM_201596.3	MANE Select	c.1511C>T	p.Thr504Ile	missense	Exon 14 of 14	NP_963890.2	Q08289-1
CACNB2	NM_201590.3	MANE Plus Clinical	c.1349C>T	p.Thr450Ile	missense	Exon 13 of 13	NP_963884.2	Q08289-3
CACNB2	NM_201597.3		c.1439C>T	p.Thr480Ile	missense	Exon 14 of 14	NP_963891.1	Q08289-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.1511C>T	p.Thr504Ile	missense	Exon 14 of 14	ENSP00000320025.8	Q08289-1
CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.1349C>T	p.Thr450Ile	missense	Exon 13 of 13	ENSP00000366546.4	Q08289-3
CACNB2	ENST00000352115.10	TSL:1	c.1439C>T	p.Thr480Ile	missense	Exon 14 of 14	ENSP00000344474.6	Q08289-8

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

253

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000787

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00300

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00148

AC:

373

AN:

251302

AF XY:

0.00153

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00282

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00288

AC:

4214

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

2022

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33478

American (AMR)

AF:

0.000961

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00358

AC:

3981

AN:

1111990

Other (OTH)

AF:

0.00235

AC:

142

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

239

478

716

955

1194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

150

300

450

600

750

<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:

0.00166

AC:

253

AN:

152196

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

106

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41534

American (AMR)

AF:

0.000786

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00300

AC:

204

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00264

Hom.:

Bravo

AF:

0.00168

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00157

AC:

191

EpiCase

AF:

0.00316

EpiControl

AF:

0.00249

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (4)

Brugada syndrome 4 (2)

Brugada syndrome (1)

CACNB2-related disorder (1)

Cardiovascular phenotype (1)

Long QT syndrome (1)

Ventricular tachycardia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.094

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.060

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.037

MetaRNN

Benign

0.0082

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.90

PhyloP100

0.90

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.67

REVEL

Benign

0.13

Sift

Benign

0.19

Sift4G

Benign

0.21

Polyphen

0.45

Vest4

0.050

MVP

0.88

MPC

0.22

ClinPred

0.011

GERP RS

3.6

Varity_R

0.086

gMVP

0.20

Mutation Taster

=97/3

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over