rs778426010

Positions:

chr10-18527668-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_201596.3(CACNB2):c.1025T>C(p.Ile342Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 8.02

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 -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.769

BP6

Variant 10-18527668-T-C is Benign according to our data. Variant chr10-18527668-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411701.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CACNB2	NM_201596.3 linkuse as main transcript	c.1025T>C	p.Ile342Thr	missense_variant	10/14	ENST00000324631.13
CACNB2	NM_201590.3 linkuse as main transcript	c.863T>C	p.Ile288Thr	missense_variant	9/13	ENST00000377329.10
LOC124902386	XR_007062076.1 linkuse as main transcript	n.84-8838A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	UniProt
CACNB2	ENST00000324631.13 linkuse as main transcript	c.1025T>C	p.Ile342Thr	missense_variant	10/14	1	NM_201596.3	Q08289-1
CACNB2	ENST00000377329.10 linkuse as main transcript	c.863T>C	p.Ile288Thr	missense_variant	9/13	1	NM_201590.3	Q08289-3
	ENST00000425669.1 linkuse as main transcript	n.482+11526A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251192

Hom.:

AF XY:

0.0000884

AC XY:

AN XY:

135768

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:

0.000196

Gnomad FIN exome

AF:

0.000419

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1461276

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000705

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.000413

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000566

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000752

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000576

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Brugada syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 20, 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 missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 411701). This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. This variant is present in population databases (rs778426010, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 288 of the CACNB2 protein (p.Ile288Thr). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

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

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

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

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.77

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

MetaSVM

Benign

-0.37

MutationAssessor

Benign

2.0

M;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-3.4

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

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

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

Sift4G

Benign

0.074

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

Polyphen

0.15

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

Vest4

0.95

MutPred

0.76

Gain of phosphorylation at I342 (P = 0.0502);.;.;.;.;.;.;.;.;.;.;

MVP

0.84

MPC

0.89

ClinPred

0.33

GERP RS

5.7

Varity_R

0.69

gMVP

0.81

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