rs1554843232

Positions:

chr10-18539666-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000324631.13(CACNB2):c.1925T>C(p.Ile642Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,460,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I642R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CACNB2
ENST00000324631.13 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.33

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19461146).

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB2	NM_201596.3 linkuse as main transcript	c.1925T>C	p.Ile642Thr	missense_variant	14/14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3 linkuse as main transcript	c.1763T>C	p.Ile588Thr	missense_variant	13/13	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNB2	ENST00000324631.13 linkuse as main transcript	c.1925T>C	p.Ile642Thr	missense_variant	14/14	1	NM_201596.3	ENSP00000320025	Q08289-1
CACNB2	ENST00000377329.10 linkuse as main transcript	c.1763T>C	p.Ile588Thr	missense_variant	13/13	1	NM_201590.3	ENSP00000366546	Q08289-3
	ENST00000425669.1 linkuse as main transcript	n.377-367A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250044

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135378

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1460740

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726702

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brugada syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 18, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 588 of the CACNB2 protein (p.Ile588Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 469643). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2021

The p.I588T variant (also known as c.1763T>C), located in coding exon 13 of the CACNB2 gene, results from a T to C substitution at nucleotide position 1763. The isoleucine at codon 588 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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

0.084

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Benign

-0.19

CADD

Benign

7.7

DANN

Benign

0.96

DEOGEN2

Benign

0.075

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

Eigen

Benign

-0.19

Eigen_PC

Benign

0.0025

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.86

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

M_CAP

Benign

0.020

MetaRNN

Benign

0.15

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

MetaSVM

Benign

-0.30

MutationAssessor

Benign

0.34

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

MutationTaster

Benign

0.90

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

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.52

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

REVEL

Uncertain

0.38

Sift

Benign

0.098

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

Sift4G

Benign

0.99

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

Polyphen

0.22

B;B;B;.;.;B;.;.;.;B;B;.;.;.

Vest4

0.059

MutPred

0.19

Gain of phosphorylation at I642 (P = 0.0287);.;.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.91

MPC

0.26

ClinPred

0.064

GERP RS

5.2

Varity_R

0.063

gMVP

0.074

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