Genetic Variant NM_201596.3:c.121-1G>T (chr10-18150882-G-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.121-1G>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 0.0073 ( 0 hom., cov: 0)

Exomes 𝑓: 0.035 ( 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, single submitter U:1

Conservation

PhyloP100: 4.39

Publications

1 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:

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.

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	Effect	Exon Rank	Protein	UniProt
CACNB2	NM_201596.3	MANE Select	c.121-1G>T	splice_acceptor intron	N/A	NP_963890.2	Q08289-1
CACNB2	NM_201597.3		c.121-1G>T	splice_acceptor intron	N/A	NP_963891.1	Q08289-8
CACNB2	NM_201571.4		c.37-1G>T	splice_acceptor intron	N/A	NP_963865.2	Q08289-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.121-1G>T	splice_acceptor intron	N/A	ENSP00000320025.8	Q08289-1
CACNB2	ENST00000352115.10	TSL:1	c.121-1G>T	splice_acceptor intron	N/A	ENSP00000344474.6	Q08289-8
CACNB2	ENST00000282343.13	TSL:1	c.37-1G>T	splice_acceptor intron	N/A	ENSP00000282343.8	Q08289-4

Frequencies

GnomAD3 genomes

AF:

0.00728

AC:

180

AN:

24742

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00493

Gnomad AMI

AF:

0.00538

Gnomad AMR

AF:

0.00943

Gnomad ASJ

AF:

0.00256

Gnomad EAS

AF:

0.00804

Gnomad SAS

AF:

0.00499

Gnomad FIN

AF:

0.0178

Gnomad MID

AF:

0.0263

Gnomad NFE

AF:

0.00783

Gnomad OTH

AF:

0.00602

GnomAD2 exomes

AF:

0.000619

AC:

AN:

71112

AF XY:

0.000517

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.000400

Gnomad EAS exome

AF:

0.000970

Gnomad FIN exome

AF:

0.000178

Gnomad NFE exome

AF:

0.000500

Gnomad OTH exome

AF:

0.000734

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0353

AC:

10107

AN:

286308

Hom.:

Cov.:

AF XY:

0.0320

AC XY:

4841

AN XY:

151194

show subpopulations

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

African (AFR)

AF:

0.0193

AC:

148

AN:

7682

American (AMR)

AF:

0.00835

AC:

AN:

11378

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

7986

East Asian (EAS)

AF:

0.00660

AC:

111

AN:

16822

South Asian (SAS)

AF:

0.0229

AC:

311

AN:

13600

European-Finnish (FIN)

AF:

0.00275

AC:

AN:

18540

Middle Eastern (MID)

AF:

0.0183

AC:

AN:

1090

European-Non Finnish (NFE)

AF:

0.0458

AC:

8925

AN:

195070

Other (OTH)

AF:

0.0245

AC:

347

AN:

14140

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.287

Heterozygous variant carriers

791

1582

2374

3165

3956

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

430

860

1290

1720

2150

<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:

0.00735

AC:

182

AN:

24770

Hom.:

Cov.:

AF XY:

0.00774

AC XY:

AN XY:

11630

show subpopulations

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

African (AFR)

AF:

0.00507

AC:

AN:

6118

American (AMR)

AF:

0.00944

AC:

AN:

2436

Ashkenazi Jewish (ASJ)

AF:

0.00256

AC:

AN:

782

East Asian (EAS)

AF:

0.00804

AC:

AN:

622

South Asian (SAS)

AF:

0.00627

AC:

AN:

798

European-Finnish (FIN)

AF:

0.0178

AC:

AN:

676

Middle Eastern (MID)

AF:

0.0250

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00783

AC:

100

AN:

12778

Other (OTH)

AF:

0.00599

AC:

AN:

334

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.339

Heterozygous variant carriers

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

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Brugada syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.95

PhyloP100

4.4

GERP RS

5.7

Mutation Taster

=8/92

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.97

Position offset: 14

DS_AL_spliceai

1.0

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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