chr1-115725533-C-T

Position:

chr1-115725533-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001232.4(CASQ2):c.758G>A(p.Arg253His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,407,546 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 1 hom., cov: 30)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

CASQ2
NM_001232.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 3.29

Variant links:

Genes affected

CASQ2 (HGNC:1513): (calsequestrin 2) The protein encoded by this gene specifies the cardiac muscle family member of the calsequestrin family. Calsequestrin is localized to the sarcoplasmic reticulum in cardiac and slow skeletal muscle cells. The protein is a calcium binding protein that stores calcium for muscle function. Mutations in this gene cause stress-induced polymorphic ventricular tachycardia, also referred to as catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2), a disease characterized by bidirectional ventricular tachycardia that may lead to cardiac arrest. [provided by RefSeq, Jul 2008]

CASQ2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2791785).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASQ2	NM_001232.4 linkuse as main transcript	c.758G>A	p.Arg253His	missense_variant	7/11	ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6 linkuse as main transcript	c.758G>A	p.Arg253His	missense_variant	7/11	1	NM_001232.4	ENSP00000261448	P1	O14958-1
CASQ2	ENST00000488931.2 linkuse as main transcript	c.*130G>A		3_prime_UTR_variant, NMD_transcript_variant	9/13	3		ENSP00000518226

Frequencies

GnomAD3 genomes

AF:

0.000116

AC:

AN:

129072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000302

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000371

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000907

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000934

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000846

AC:

AN:

248204

Hom.:

AF XY:

0.0000894

AC XY:

AN XY:

134216

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000415

AC:

AN:

1278398

Hom.:

Cov.:

AF XY:

0.0000451

AC XY:

AN XY:

643330

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000454

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000106

Gnomad4 SAS exome

AF:

0.0000726

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000390

Gnomad4 OTH exome

AF:

0.0000559

GnomAD4 genome

AF:

0.000116

AC:

AN:

129148

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

60630

show subpopulations

Gnomad4 AFR

AF:

0.0000302

Gnomad4 AMR

AF:

0.000370

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000909

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000934

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000746

Hom.:

ExAC

AF:

0.0000824

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 28, 2014

The Arg253His variant in CASQ2 has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 1/196 Toscani Italian chromosomes by the 1000 Genomes Project (dbSNP rs199571249). Computational analyses (bioche mical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do no t provide strong support for or against an impact to the protein. Additional inf ormation is needed to fully assess the clinical significance of the Arg253His va riant. -

Catecholaminergic polymorphic ventricular tachycardia 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Catecholaminergic polymorphic ventricular tachycardia 1;C2677794:Catecholaminergic polymorphic ventricular tachycardia 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 25, 2021

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 08, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 253 of the CASQ2 protein (p.Arg253His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CASQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 162812). 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. 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 13, 2023

The p.R253H variant (also known as c.758G>A), located in coding exon 7 of the CASQ2 gene, results from a G to A substitution at nucleotide position 758. The arginine at codon 253 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in cohorts not selected for the presence of cardiac disease; however, clinical details were limited (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10; Bajaj A et al. Hum Genomics, 2022 Aug;16:30). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

0.094

BayesDel_addAF

Benign

-0.0022

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.012

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.41

Sift

Uncertain

0.028

Sift4G

Uncertain

0.043

Polyphen

0.17

Vest4

0.47

MVP

0.90

MPC

0.058

ClinPred

0.11

GERP RS

5.3

Varity_R

0.38

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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