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GeneBe

10-18500899-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_201596.3(CACNB2):c.544A>G(p.Met182Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.46
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.29676473).
BS2
High AC in GnomAdExome at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CACNB2NM_201596.3 linkuse as main transcriptc.544A>G p.Met182Val missense_variant 5/14 ENST00000324631.13
CACNB2NM_201590.3 linkuse as main transcriptc.382A>G p.Met128Val missense_variant 4/13 ENST00000377329.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CACNB2ENST00000324631.13 linkuse as main transcriptc.544A>G p.Met182Val missense_variant 5/141 NM_201596.3 Q08289-1
CACNB2ENST00000377329.10 linkuse as main transcriptc.382A>G p.Met128Val missense_variant 4/131 NM_201590.3 Q08289-3

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152210
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251256
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135790
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000465
AC:
68
AN:
1461792
Hom.:
0
Cov.:
32
AF XY:
0.0000509
AC XY:
37
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.0000549
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152210
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000387
Hom.:
0
Bravo
AF:
0.0000151
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Brugada syndrome 4 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 19, 2023This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 128 of the CACNB2 protein (p.Met128Val). This variant is present in population databases (rs775466397, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 411702). 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 with a negative predictive value of 80%. 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. -
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsNov 09, 2021- -
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterresearchCSER _CC_NCGL, University of WashingtonOct 01, 2016Found in patient having exome sequencing for an unrelated indication. No known history of Brugada syndrome. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 07, 2024The p.M128V variant (also known as c.382A>G), located in coding exon 4 of the CACNB2 gene, results from an A to G substitution at nucleotide position 382. The methionine at codon 128 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.067
T
BayesDel_noAF
Benign
-0.15
Cadd
Benign
21
Dann
Uncertain
0.98
DEOGEN2
Benign
0.15
T;.;.;.;.;T;.;.;.;.;.;.;.
Eigen
Benign
0.14
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.91
D;D;.;D;D;D;D;D;D;D;D;.;D
M_CAP
Benign
0.062
D
MetaRNN
Benign
0.30
T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.30
T
MutationAssessor
Benign
1.0
L;L;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-1.0
N;N;.;.;N;.;N;N;N;.;N;.;.
REVEL
Uncertain
0.32
Sift
Uncertain
0.024
D;D;.;.;D;.;D;D;D;.;D;.;.
Sift4G
Uncertain
0.037
D;D;.;.;D;D;D;D;D;T;D;.;.
Polyphen
0.017
B;B;.;.;B;.;.;B;B;B;.;.;.
Vest4
0.48
MVP
0.83
MPC
0.21
ClinPred
0.15
T
GERP RS
5.9
Varity_R
0.37
gMVP
0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs775466397; hg19: chr10-18789828; COSMIC: COSV56619823; COSMIC: COSV56619823; API