rs372277783

Positions:

• chr10-18539654-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_201596.3(CACNB2):​c.1913A>G​(p.Asp638Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,338 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: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.27

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]

ENSG00000240291 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21948546).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.1913A>G	p.Asp638Gly	missense_variant	14/14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.1751A>G	p.Asp584Gly	missense_variant	13/13	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.1913A>G	p.Asp638Gly	missense_variant	14/14	1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10	c.1751A>G	p.Asp584Gly	missense_variant	13/13	1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461338 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727008

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2018

This variant is present in population databases (rs372277783, ExAC 0.002%). This sequence change replaces aspartic acid with glycine at codon 584 of the CACNB2 protein (p.Asp584Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant has not been reported in the literature in individuals with CACNB2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	Benign	0.099
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;T;.;.;.;T;T;.;.;.;T;.;.
Eigen	Benign	0.057
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T;T;.;T;T;T;T;T;T;T;D;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.81	L;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.18	N;N;N;.;.;N;.;.;N;N;N;.;N;.
REVEL	Uncertain	0.42
Sift	Benign	0.60	T;T;T;.;.;T;.;.;T;T;T;.;T;.
Sift4G	Benign	0.37	T;T;T;.;.;T;T;T;T;T;T;T;T;.
Polyphen		0.77	P;P;B;.;.;P;.;.;.;B;P;.;.;.
Vest4		0.32
MVP		0.88
MPC		0.51
ClinPred		0.43	T
GERP RS		5.2
Varity_R		0.22
gMVP		0.19

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

Other links and lift over

dbSNP: rs372277783; hg19: chr10-18828583;