rs1554835149

Positions:

• chr10-18514275-A-C

Variant summary

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

The NM_201596.3(CACNB2):​c.710A>C​(p.Asn237Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N237N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

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=0.08712819).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.710A>C	p.Asn237Thr	missense_variant	7/14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.548A>C	p.Asn183Thr	missense_variant	6/13	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.710A>C	p.Asn237Thr	missense_variant	7/14	1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10	c.548A>C	p.Asn183Thr	missense_variant	6/13	1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Oct 03, 2017

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. 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: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CACNB2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with threonine at codon 183 of the CACNB2 protein (p.Asn183Thr). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.0077	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T;.;.;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.0071
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.087	T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.0	L;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.66	N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.12	T;T;T;T;T
Sift4G	Benign	0.42	T;T;T;T;T
Polyphen		0.030	B;B;.;B;.
Vest4		0.27
MutPred		0.31		Gain of sheet (P = 0.0266);.;.;.;.;
MVP		0.83
MPC		0.21
ClinPred		0.21	T
GERP RS		4.8
Varity_R		0.089
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554835149; hg19: chr10-18803204;