10-18527637-G-T

Position:

chr10-18527637-G-T

Variant summary

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

The NM_201596.3(CACNB2):c.994G>T(p.Val332Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,830 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 10.0

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 links:

(HGNC:):

links:

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=0.35105228).

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CACNB2	NM_201596.3 linkuse as main transcript	c.994G>T	p.Val332Leu	missense_variant	10/14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3 linkuse as main transcript	c.832G>T	p.Val278Leu	missense_variant	9/13	ENST00000377329.10	NP_963884.2
LOC124902386	XR_007062076.1 linkuse as main transcript	n.84-8807C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNB2	ENST00000324631.13 linkuse as main transcript	c.994G>T	p.Val332Leu	missense_variant	10/14	1	NM_201596.3	ENSP00000320025	Q08289-1
CACNB2	ENST00000377329.10 linkuse as main transcript	c.832G>T	p.Val278Leu	missense_variant	9/13	1	NM_201590.3	ENSP00000366546	Q08289-3
	ENST00000425669.1 linkuse as main transcript	n.482+11557C>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251296

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461772

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000949

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brugada syndrome 4

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	CACNB2 NM_201590.2 exon 9 p.Val278Leu (c.832G>T): This variant has not been reported in the literature but is present in 0.01% (2/18382) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/10-18816566-G-T). This variant is present in ClinVar (Variation ID:537365). Evolutionary conservation suggests that this variant may impact the protein; however, computational predictive tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 278 of the CACNB2 protein (p.Val278Leu). This variant is present in population databases (rs369543094, gnomAD 0.01%). 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: 537365). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.076

T;.;.;.;.;T;.;.;.;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;.;D;D;D;D;D;D;D;D

M_CAP

Benign

0.0090

MetaRNN

Benign

0.35

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.0050

N;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.2

N;N;.;.;N;.;N;N;N;N;.

REVEL

Benign

0.22

Sift

Benign

0.21

T;T;.;.;T;.;T;T;T;T;.

Sift4G

Benign

0.43

T;T;.;.;T;T;T;T;T;T;.

Polyphen

0.091

B;B;.;.;B;.;.;D;P;.;.

Vest4

0.77

MutPred

0.68

Gain of helix (P = 0.027);.;.;.;.;.;.;.;.;.;.;

MVP

0.56

MPC

0.78

ClinPred

0.53

GERP RS

5.7

Varity_R

0.28

gMVP

0.64

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over