rs199750975

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BS1_Supporting

The NM_001232.4(CASQ2):c.338G>A(p.Ser113Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000819 in 1,611,652 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S113R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

CASQ2
NM_001232.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 6.70

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000774 (113/1459538) while in subpopulation AFR AF= 0.000718 (24/33432). AF 95% confidence interval is 0.000494. There are 0 homozygotes in gnomad4_exome. There are 58 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASQ2	NM_001232.4 link	c.338G>A	p.Ser113Asn	missense_variant	Exon 3 of 11	ENST00000261448.6	NP_001223.2	O14958-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6 link	c.338G>A	p.Ser113Asn	missense_variant	Exon 3 of 11	1	NM_001232.4	ENSP00000261448.5		O14958-1
CASQ2	ENST00000488931.2 link	n.62G>A		non_coding_transcript_exon_variant	Exon 4 of 13	3		ENSP00000518226.1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000588

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251210

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.000246

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:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000774

AC:

113

AN:

1459538

Hom.:

Cov.:

AF XY:

0.0000799

AC XY:

AN XY:

726234

show subpopulations

Gnomad4 AFR exome

AF:

0.000718

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000757

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000125

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.000314

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000197

Hom.:

Bravo

AF:

0.000200

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Dec 31, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser113Asn variant in CASQ2 has not been reported in any other families wit h cardiomyopathy, but has been identified in 3/10514 African chromosomes and 2/6 6974 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs199750975). Computational prediction tools and cons ervation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ser113Asn variant is unc ertain. -

Oct 23, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CASQ2 c.338G>A (p.Ser113Asn) variant involves the alteration of a conserved nucleotide and 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Although the variant is located outsed of any know domain or repeat, the impact of this change on the protein have yet to be functionally assessed. This variant was found in 12/276958 control chromosomes at a frequency of 0.0000433, which does not exceed the estimated maximal expected allele frequency of a pathogenic CASQ2 variant (0.0044721). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)", until additional information becomes available. -

Catecholaminergic polymorphic ventricular tachycardia 2

Uncertain:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 29, 2016

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:2

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 05, 2015

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser113Asn (AGC>AAC): c.338 G>A in exon 3 of the CASQ2 gene (NM_001232.3). The S113N variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The S113N variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, this substitution occurs at a position that is conserved among mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the S113N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, missense mutations in nearby residues have not been reported, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s). -

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

Uncertain:1

Nov 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 113 of the CASQ2 protein (p.Ser113Asn). This variant is present in population databases (rs199750975, gnomAD 0.02%). 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: 162820). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CASQ2 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

Sep 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S113N variant (also known as c.338G>A), located in coding exon 3 of the CASQ2 gene, results from a G to A substitution at nucleotide position 338. The serine at codon 113 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in cardiomyopathy cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:[ePub ahead of print]; Akinrinade O et al. J Cardiovasc Transl Res, 2023 Jul:[ePub ahead of print]). This amino acid position is highly conserved in available 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

Pathogenic

0.73

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.018

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.7

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.44

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.90

MVP

0.62

MPC

0.31

ClinPred

0.33

GERP RS

6.0

Varity_R

0.78

gMVP

0.77

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