rs142036299

Positions:

chr1-115726999-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 4P and 7B. PM2PM5BP4_ModerateBP6BS1

The NM_001232.4(CASQ2):c.730C>T(p.His244Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 1,608,828 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H244C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00073 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 1 hom. )

Consequence

CASQ2
NM_001232.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.28

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-115726998-T-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.07780275).

BP6

Variant 1-115726999-G-A is Benign according to our data. Variant chr1-115726999-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227210.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr1-115726999-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00073 (111/151972) while in subpopulation AFR AF= 0.00241 (100/41444). AF 95% confidence interval is 0.00203. There are 0 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASQ2	NM_001232.4 linkuse as main transcript	c.730C>T	p.His244Tyr	missense_variant	6/11	ENST00000261448.6	NP_001223.2	O14958-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CASQ2	ENST00000261448.6 linkuse as main transcript	c.730C>T	p.His244Tyr	missense_variant	6/11	1	NM_001232.4	ENSP00000261448.5	O14958-1
CASQ2	ENST00000488931.2 linkuse as main transcript	n.*102C>T		non_coding_transcript_exon_variant	8/13	3		ENSP00000518226.1
CASQ2	ENST00000488931.2 linkuse as main transcript	n.*102C>T		3_prime_UTR_variant	8/13	3		ENSP00000518226.1

Frequencies

GnomAD3 genomes

AF:

0.000731

AC:

111

AN:

151854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

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:

0.0000147

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.000188

AC:

AN:

250308

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135290

show subpopulations

Gnomad AFR exome

AF:

0.00235

Gnomad AMR exome

AF:

0.000232

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:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000680

AC:

AN:

1456856

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

724742

show subpopulations

Gnomad4 AFR exome

AF:

0.00204

Gnomad4 AMR exome

AF:

0.000224

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:

0.00

Gnomad4 OTH exome

AF:

0.000350

GnomAD4 genome

AF:

0.000730

AC:

111

AN:

151972

Hom.:

Cov.:

AF XY:

0.000794

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.00241

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000950

Alfa

AF:

0.000149

Hom.:

Bravo

AF:

0.000733

ExAC

AF:

0.000214

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 16, 2023

The CASQ2 c.730_731delinsTG; p.His244Cys variant, to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 228471). This variant consists of two single nucleotide variants, c.730C>T (rs142036299) and c.731A>G (rs28730716), in adjacent nucleotides on the same chromosome. The individual variants, c.730C>T and c.731A>G, are found in the African population with overall allele frequencies of 0.23% (54/23932 alleles) and 8.3% (1990/23868 alleles), respectively, in the Genome Aggregation Database, and available data indicates that c.730C>T may always occur with c.731A>G. The histidine at codon 244 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.His244Cys variant is uncertain at this time. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 13, 2021

The p.H244Y variant (also known as c.730C>T), located in coding exon 6 of the CASQ2 gene, results from a C to T substitution at nucleotide position 730. The histidine at codon 244 is replaced by tyrosine, an amino acid with some similar properties. This alteration has been reported in a proband with left ventricular non-compaction (LVNC) who also carried alterations in other cardiac-related genes (Hoedemaekers YM et al. Circ Cardiovasc Genet, 2010 Jun;3:232-9). This variant has also been reported in a sudden unexplained death cohort and a catecholaminergic polymorphic ventricular tachycardia (CPVT) cohort; however, clinical details were limited (Sanchez O et al. PLoS ONE, 2016 Dec;11:e0167358; Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:). This amino acid position is highly 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 05, 2015

p.His244Tyr in exon 6 of CASQ2: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (25/9422) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs142036299). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.068

MetaRNN

Benign

0.078

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.76

MVP

0.98

MPC

0.29

ClinPred

0.081

GERP RS

5.8

Varity_R

0.75

gMVP

0.90

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