NM_201596.3:c.1591C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_201596.3(CACNB2):​c.1591C>G​(p.Arg531Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R531C) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 30)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

1
9
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.96

Publications

10 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: Benign. The variant received -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.20125988).
BP6
Variant 10-18539332-C-G is Benign according to our data. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294. Variant chr10-18539332-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 660294.
BS2
High AC in GnomAdExome4 at 7 AD,Unknown gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNB2NM_201596.3 linkc.1591C>G p.Arg531Gly missense_variant Exon 14 of 14 ENST00000324631.13 NP_963890.2 Q08289-1
CACNB2NM_201590.3 linkc.1429C>G p.Arg477Gly missense_variant Exon 13 of 13 ENST00000377329.10 NP_963884.2 Q08289-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNB2ENST00000324631.13 linkc.1591C>G p.Arg531Gly missense_variant Exon 14 of 14 1 NM_201596.3 ENSP00000320025.8 Q08289-1
CACNB2ENST00000377329.10 linkc.1429C>G p.Arg477Gly missense_variant Exon 13 of 13 1 NM_201590.3 ENSP00000366546.4 Q08289-3

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152120
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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
GnomAD2 exomes
AF:
0.0000239
AC:
6
AN:
251354
AF XY:
0.0000221
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000173
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461868
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727236
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.000134
AC:
6
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111994
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.511
Heterozygous variant carriers
0
1
2
2
3
4
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
AF:
0.0000197
AC:
3
AN:
152120
Hom.:
0
Cov.:
30
AF XY:
0.0000269
AC XY:
2
AN XY:
74310
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41422
American (AMR)
AF:
0.000196
AC:
3
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68024
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jul 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Brugada syndrome 4 Uncertain:1
Aug 07, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNB2 protein function. ClinVar contains an entry for this variant (Variation ID: 660294). This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 477 of the CACNB2 protein (p.Arg477Gly). -

Cardiovascular phenotype Benign:1
Oct 03, 2024
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.039
T
BayesDel_noAF
Uncertain
0.090
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.14
T;.;T;.;.;.;T;T;.;.;.;T;.;.
Eigen
Benign
0.19
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.20
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.15
T
MutationAssessor
Uncertain
2.2
M;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100
3.0
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-1.1
N;N;N;.;.;N;.;.;N;N;N;.;N;.
REVEL
Uncertain
0.32
Sift
Benign
0.15
T;T;T;.;.;T;.;.;T;T;T;.;T;.
Sift4G
Benign
0.18
T;T;T;.;.;T;T;T;T;T;T;D;T;.
Polyphen
0.99
D;D;D;.;.;D;.;.;.;D;P;.;.;.
Vest4
0.68
MutPred
0.18
Loss of MoRF binding (P = 0.0075);.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP
0.88
MPC
0.77
ClinPred
0.25
T
GERP RS
4.9
Varity_R
0.22
gMVP
0.48
Mutation Taster
=55/45
polymorphism

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: rs202152674; hg19: chr10-18828261; API