rs397516641

Variant names:

• chr1-115701253-ATCG-A
• rs397516641
• NM_001232.4:c.1185_1187delCGA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_001232.4(CASQ2):​c.1185_1187delCGA​(p.Asp396del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00613 in 1,600,538 control chromosomes in the GnomAD database, including 55 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D395D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0064 (48 hom.)
• Consequence: CASQ2 NM_001232.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:14
• Conservation: PhyloP100: 2.40
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• catecholaminergic polymorphic ventricular tachycardia 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Genomics England PanelApp
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001232.4
• BP6: Variant 1-115701253-ATCG-A is Benign according to our data. Variant chr1-115701253-ATCG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44158.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00388 (591/152222) while in subpopulation NFE AF = 0.00628 (427/68006). AF 95% confidence interval is 0.00579. There are 7 homozygotes in GnomAd4. There are 269 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001232.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASQ2	NM_001232.4	MANE Select	c.1185_1187delCGA	p.Asp396del	disruptive_inframe_deletion	Exon 11 of 11	NP_001223.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASQ2	ENST00000261448.6	TSL:1 MANE Select	c.1185_1187delCGA	p.Asp396del	disruptive_inframe_deletion	Exon 11 of 11	ENSP00000261448.5
	CASQ2	ENST00000713711.1		c.1326_1328delCGA	p.Asp443del	disruptive_inframe_deletion	Exon 12 of 12	ENSP00000519014.1
	CASQ2	ENST00000713728.1		c.909_911delCGA	p.Asp304del	disruptive_inframe_deletion	Exon 12 of 12	ENSP00000519032.1

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 591 AN: 152104 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00628

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00464 AC: 1161 AN: 250482 AF XY: 0.00426

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00665

Gnomad NFE exome AF: 0.00784

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00637 AC: 9221 AN: 1448316 Hom.: 48 AF XY: 0.00608 AC XY: 4386 AN XY: 720998

African (AFR) AF: 0.000936 AC: 31 AN: 33132

American (AMR) AF: 0.00170 AC: 76 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26022

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39634

South Asian (SAS) AF: 0.000874 AC: 75 AN: 85784

European-Finnish (FIN) AF: 0.00675 AC: 359 AN: 53172

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5714

European-Non Finnish (NFE) AF: 0.00764 AC: 8404 AN: 1100312

Other (OTH) AF: 0.00456 AC: 273 AN: 59920

GnomAD4 genome AF: 0.00388 AC: 591 AN: 152222 Hom.: 7 Cov.: 31 AF XY: 0.00361 AC XY: 269 AN XY: 74418

African (AFR) AF: 0.00144 AC: 60 AN: 41530

American (AMR) AF: 0.00190 AC: 29 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4808

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00628 AC: 427 AN: 68006

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00356 Hom.: 0

Bravo AF: 0.00361

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00464

EpiControl AF: 0.00500

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 27, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CASQ2 c.1185_1187delCGA leads to an in-frame deletion of one aspartic acid residue in a repetitive region of five aspartic acids in the penultimate exon. This variant was found in 665/121072 control chromosomes (including 5 homozygotes) from the broad and large populations of ExAC at a frequency of 0.0054926, which is significantly greater than the maximal expected frequency of a pathogenic CASQ2 allele (0.0044721) in this gene, suggesting this variant is benign. The variants allele frequency was highest in the European (Non-Finnish) sub-population with an allele frequency of 0.0083 (553/66608 chromosomes) including 5 homozygotes. The variant did not segregate with cardiological phenotype LVNC (Left Ventricular Non-Compaction) in two reported families (Hoedemaekers_2012) and it was also found to co-occur with a likely pathogenic variant (LMNA c.1146C>T) in one DCM patient (Pugh_2014), strongly supporting a benign classification for the variant of interest. It has also been classified as likely benign by one lab in ClinVar. Taken together, this variant has been classified as Benign.

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CASQ2: BS2

not specified Benign:5

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 27, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Nov 28, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asp398del in exon 11 of CASQ2: This variant is an in-frame deletion of amino acid 398 at the very end of the last exon. It is not expected to have clinical s ignificance because it has been identified in 0.8% (557/67556) European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs397516641). At this frequency this variant would explain more than half o f all cases of CPVT (an autosomal recessive condition with an estimated prevalen ce of 0.01%). This is highly unlikely given that multiple different variants hav e been associated with this disorder.

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Catecholaminergic polymorphic ventricular tachycardia 2 Uncertain:1 Benign:2

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CASQ2 NM_001232.3 exon 11 p.Asp398del (c.1194_1196delTGA): This variant has been reported in the literature in at least 2 individuals with Left Ventricular Noncompaction (LVNC), but did not segregate with disease in affected family members. This variant was also identified in at least 1 individual with LVNC and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (Hoedemaekers 2010 PMID:20530761, Egan 2013 PMID:23476865). This variant is present in 0.7% (956/126210) of European alleles, including 8 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs751885773). This variant is present in ClinVar (Variation ID:190752). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an in-frame deletion of 1 amino acid at position 398 and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Mar 07, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 17, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Uncertain:1

Oct 18, 2013

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thec.1185_1187delvariant (also known as p.D395del) is located in codingexon 11 of the CASQ2 gene.This variant results from an in-frame 3 basepair deletion between nucleotide positions 1185 and 1187. This results in the deletion of an aspartic acid residue at codon 395. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), the 1000 Genomes Project and the NHLBI Exome Sequencing Project (ESP). In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at these positions. This amino acid position is not well conserved based on available sequence alignment. Since supporting evidence for this variant is limited at this time, the clinical significance of this variant remains unclear.​

Cardiomyopathy Benign:1

Nov 17, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary dilated cardiomyopathy Benign:1

May 14, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs397516641; hg19: chr1-116243874; COSMIC: COSV106082398; COSMIC: COSV106082398;