dbSNP rs750396182: CACNB2:c.121-2A>G (chr10-18150881-A-G) – 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>G variant causes a splice acceptor, intron change. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000067 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CACNB2
NM_201596.3 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

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>G		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>G		splice_acceptor_variant, intron_variant	Intron 1 of 13	1	NM_201596.3	ENSP00000320025.8		Q08289-1

Frequencies

GnomAD3 genomes

AF:

0.0000674

AC:

AN:

14830

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000213

AC:

AN:

282156

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

147544

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

7502

American (AMR)

AF:

0.00

AC:

AN:

9462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7344

East Asian (EAS)

AF:

0.00

AC:

AN:

16494

South Asian (SAS)

AF:

0.000100

AC:

AN:

9978

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1054

European-Non Finnish (NFE)

AF:

0.0000250

AC:

AN:

200168

Other (OTH)

AF:

0.00

AC:

AN:

14022

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.001490), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000674

AC:

AN:

14830

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

7434

show subpopulations

African (AFR)

AF:

0.000263

AC:

AN:

3796

American (AMR)

AF:

0.00

AC:

AN:

1590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

406

East Asian (EAS)

AF:

0.00

AC:

AN:

354

South Asian (SAS)

AF:

0.00

AC:

AN:

556

European-Finnish (FIN)

AF:

0.00

AC:

AN:

604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

7204

Other (OTH)

AF:

0.00

AC:

AN:

224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over