rs200260399

Positions:

• chr10-18539633-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.1892A>G​(p.Lys631Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,674 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 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.83

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]

(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=0.11504209).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.1892A>G	p.Lys631Arg	missense_variant	14/14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.1730A>G	p.Lys577Arg	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.1892A>G	p.Lys631Arg	missense_variant	14/14	1	NM_201596.3	ENSP00000320025
CACNB2	ENST00000377329.10	c.1730A>G	p.Lys577Arg	missense_variant	13/13	1	NM_201590.3	ENSP00000366546
	ENST00000425669.1	n.377-334T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152070 Hom.: 0 Cov.: 30

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461604 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727102

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152070 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74264

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: 0.00

Gnomad4 OTH AF: 0.000478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 14, 2022

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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 191437). This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 577 of the CACNB2 protein (p.Lys577Arg). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.052	T;.;T;.;.;.;T;T;.;.;.;T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.085
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.92	D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.66	N;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.79	N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.020	N;N;N;.;.;N;.;.;N;N;N;.;N;.
REVEL	Benign	0.12
Sift	Benign	0.37	T;T;T;.;.;T;.;.;T;T;T;.;T;.
Sift4G	Benign	1.0	T;T;T;.;.;T;T;T;T;T;T;T;T;.
Polyphen		0.0	B;B;B;.;.;B;.;.;.;B;B;.;.;.
Vest4		0.054
MutPred		0.20		Loss of methylation at K631 (P = 0.0089);.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.81
MPC		0.17
ClinPred		0.59	D
GERP RS		4.6
Varity_R		0.11
gMVP		0.048

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: rs200260399; hg19: chr10-18828562;