NM_201596.3:c.121-1G>T

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

4
2
1
Splicing: ADA: 1.000
2

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: 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

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
CACNB2NM_201596.3 linkc.121-1G>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
CACNB2ENST00000324631.13 linkc.121-1G>T splice_acceptor_variant, intron_variant Intron 1 of 13 1 NM_201596.3 ENSP00000320025.8 Q08289-1

Frequencies

GnomAD3 genomes
AF:
0.00728
AC:
180
AN:
24742
Hom.:
0
Cov.:
0
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:
44
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.:
0
Cov.:
8
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:
95
AN:
11378
Ashkenazi Jewish (ASJ)
AF:
0.0124
AC:
99
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:
51
AN:
18540
Middle Eastern (MID)
AF:
0.0183
AC:
20
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 = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.287
Heterozygous variant carriers
0
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
0
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.:
0
Cov.:
0
AF XY:
0.00774
AC XY:
90
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:
31
AN:
6118
American (AMR)
AF:
0.00944
AC:
23
AN:
2436
Ashkenazi Jewish (ASJ)
AF:
0.00256
AC:
2
AN:
782
East Asian (EAS)
AF:
0.00804
AC:
5
AN:
622
South Asian (SAS)
AF:
0.00627
AC:
5
AN:
798
European-Finnish (FIN)
AF:
0.0178
AC:
12
AN:
676
Middle Eastern (MID)
AF:
0.0250
AC:
1
AN:
40
European-Non Finnish (NFE)
AF:
0.00783
AC:
100
AN:
12778
Other (OTH)
AF:
0.00599
AC:
2
AN:
334
⚠️ 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: 0.339
Heterozygous variant carriers
0
9
18
26
35
44
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
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

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
35
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Uncertain
0.95
D
PhyloP100
4.4
GERP RS
5.7
Mutation Taster
=8/92
disease causing

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

Other links and lift over

dbSNP: rs875989812; hg19: chr10-18439811; COSMIC: COSV106086183; API