rs139749312

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_201596.3(CACNB2):c.1178T>C(p.Ile393Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,613,286 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I393R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.27

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:

LOC124902387 (HGNC:):

LOC124902387 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CACNB2	NM_201596.3 linkuse as main transcript	c.1178T>C	p.Ile393Thr	missense_variant	11/14	ENST00000324631.13
CACNB2	NM_201590.3 linkuse as main transcript	c.1016T>C	p.Ile339Thr	missense_variant	10/13	ENST00000377329.10
LOC124902387	XR_007062077.1 linkuse as main transcript	n.598A>G		non_coding_transcript_exon_variant	1/2
LOC124902386	XR_007062076.1 linkuse as main transcript	n.83+4995A>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.1178T>C	p.Ile393Thr	missense_variant	11/14	1	NM_201596.3	Q08289-1
CACNB2	ENST00000377329.10 linkuse as main transcript	c.1016T>C	p.Ile339Thr	missense_variant	10/13	1	NM_201590.3	Q08289-3
	ENST00000425669.1 linkuse as main transcript	n.482+4995A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251364

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135864

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:

0.0000704

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461100

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726918

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:

0.0000324

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000763

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brugada syndrome 4

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 339 of the CACNB2 protein (p.Ile339Thr). This variant is present in population databases (rs139749312, gnomAD 0.006%). 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: 242259). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNB2 protein function with a negative predictive value of 80%. 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

Mar 14, 2024

The p.I339T variant (also known as c.1016T>C), located in coding exon 10 of the CACNB2 gene, results from a T to C substitution at nucleotide position 1016. The isoleucine at codon 339 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

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

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.73

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

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

2.0

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.8

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

REVEL

Pathogenic

0.74

Sift

Benign

0.037

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

Sift4G

Uncertain

0.052

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

Polyphen

0.81

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

Vest4

0.77

MVP

0.93

MPC

0.31

ClinPred

0.47

GERP RS

5.5

Varity_R

0.43

gMVP

0.73

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