Genetic Variant CACNB2:c.121-2A>T (chr10-18150881-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_201596.3(CACNB2):c.121-2A>T variant causes a splice acceptor, intron change. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.040 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0051 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNB2
NM_201596.3 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.59

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.046898637 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3 link	c.121-2A>T		splice_acceptor_variant, intron_variant	Intron 1 of 13	ENST00000324631.13	NP_963890.2	Q08289-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13 link	c.121-2A>T		splice_acceptor_variant, intron_variant	Intron 1 of 13	1	NM_201596.3	ENSP00000320025.8		Q08289-1

Frequencies

GnomAD3 genomes

AF:

0.0404

AC:

584

AN:

14454

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0343

Gnomad AMI

AF:

0.0345

Gnomad AMR

AF:

0.0348

Gnomad ASJ

AF:

0.0278

Gnomad EAS

AF:

0.0260

Gnomad SAS

AF:

0.0328

Gnomad FIN

AF:

0.0304

Gnomad MID

AF:

0.125

Gnomad NFE

AF:

0.0478

Gnomad OTH

AF:

0.0275

GnomAD2 exomes

AF:

0.000848

AC:

AN:

55412

AF XY:

0.000887

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00257

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00237

Gnomad FIN exome

AF:

0.000261

Gnomad NFE exome

AF:

0.000437

Gnomad OTH exome

AF:

0.00388

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00505

AC:

1409

AN:

278968

Hom.:

Cov.:

AF XY:

0.00495

AC XY:

722

AN XY:

145936

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00269

AC:

AN:

7446

American (AMR)

AF:

0.00436

AC:

AN:

9402

Ashkenazi Jewish (ASJ)

AF:

0.00371

AC:

AN:

7272

East Asian (EAS)

AF:

0.00158

AC:

AN:

16406

South Asian (SAS)

AF:

0.0111

AC:

109

AN:

9856

European-Finnish (FIN)

AF:

0.00162

AC:

AN:

16040

Middle Eastern (MID)

AF:

0.00288

AC:

AN:

1042

European-Non Finnish (NFE)

AF:

0.00560

AC:

1106

AN:

197596

Other (OTH)

AF:

0.00367

AC:

AN:

13908

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.285

Heterozygous variant carriers

127

253

380

506

633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

132

176

220

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0403

AC:

583

AN:

14458

Hom.:

Cov.:

AF XY:

0.0360

AC XY:

261

AN XY:

7256

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0339

AC:

126

AN:

3720

American (AMR)

AF:

0.0348

AC:

AN:

1550

Ashkenazi Jewish (ASJ)

AF:

0.0278

AC:

AN:

396

East Asian (EAS)

AF:

0.0263

AC:

AN:

342

South Asian (SAS)

AF:

0.0330

AC:

AN:

546

European-Finnish (FIN)

AF:

0.0304

AC:

AN:

592

Middle Eastern (MID)

AF:

0.125

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0478

AC:

335

AN:

7002

Other (OTH)

AF:

0.0273

AC:

AN:

220

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.341

Heterozygous variant carriers

116

145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

ExAC

AF:

0.0000336

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brugada syndrome

Uncertain:1

Mar 11, 2015

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Brugada syndrome 4

Uncertain:1

Oct 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.96

PhyloP100

6.6

GERP RS

5.7

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.97

Position offset: 15

DS_AL_spliceai

1.0

Position offset: 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