10-18150970-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_201596.3(CACNB2):​c.208C>A​(p.Arg70Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000704 in 1,419,614 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R70H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 28)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

2
7
10

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.38

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.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNB2NM_201596.3 linkc.208C>A p.Arg70Ser missense_variant Exon 2 of 14 ENST00000324631.13 NP_963890.2 Q08289-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNB2ENST00000324631.13 linkc.208C>A p.Arg70Ser missense_variant Exon 2 of 14 1 NM_201596.3 ENSP00000320025.8 Q08289-1

Frequencies

GnomAD3 genomes
Cov.:
28
GnomAD4 exome
AF:
7.04e-7
AC:
1
AN:
1419614
Hom.:
0
Cov.:
29
AF XY:
0.00000141
AC XY:
1
AN XY:
706912
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:
0
AN:
32440
American (AMR)
AF:
0.00
AC:
0
AN:
43894
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25214
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36788
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85516
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50770
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5566
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1081368
Other (OTH)
AF:
0.0000172
AC:
1
AN:
58058
⚠️ 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: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
28
Alfa
AF:
0.00
Hom.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Uncertain
0.085
D
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.19
T;.;T;.;.;.
Eigen
Benign
-0.16
Eigen_PC
Benign
0.024
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.91
D;D;D;.;D;D
M_CAP
Benign
0.073
D
MetaRNN
Uncertain
0.43
T;T;T;T;T;T
MetaSVM
Benign
-0.39
T
MutationAssessor
Benign
1.0
L;L;.;.;.;.
PhyloP100
5.4
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-2.8
D;D;N;.;.;D
REVEL
Uncertain
0.35
Sift
Benign
0.040
D;D;D;.;.;D
Sift4G
Benign
0.12
T;T;D;.;.;T
Polyphen
0.042
B;B;B;.;.;B
Vest4
0.87
MutPred
0.26
Gain of phosphorylation at R70 (P = 0.0101);Gain of phosphorylation at R70 (P = 0.0101);Gain of phosphorylation at R70 (P = 0.0101);.;.;.;
MVP
0.90
MPC
0.24
ClinPred
0.87
D
GERP RS
5.0
Varity_R
0.32
gMVP
0.41
Mutation Taster
=37/63
disease causing

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

Other links and lift over

dbSNP: rs760538597; hg19: chr10-18439899; API