rs786205272

Positions:

• chr1-115701253-ATCG-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001232.4(CASQ2):​c.1185_1187del​(p.Asp398del) variant causes a 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 Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0039 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0064 (48 hom.)
• Consequence: CASQ2 NM_001232.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13
• Conservation: PhyloP100: 2.40

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• 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 id is 44158.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=6, Uncertain_significance=3}. Variant chr1-115701253-ATCG-A is described in Lovd as [Benign]. Variant chr1-115701253-ATCG-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.1185_1187del	p.Asp398del	inframe_deletion	11/11	ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.1185_1187del	p.Asp398del	inframe_deletion	11/11	1	NM_001232.4	ENSP00000261448	P1
CASQ2	ENST00000488931.2	c.*557_*559del		3_prime_UTR_variant, NMD_transcript_variant	13/13	3		ENSP00000518226

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

GnomAD3 exomes AF: 0.00464 AC: 1161 AN: 250482 Hom.: 10 AF XY: 0.00426 AC XY: 577 AN XY: 135312

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 SAS exome AF: 0.000820

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

Gnomad4 AFR exome AF: 0.000936

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000874

Gnomad4 FIN exome AF: 0.00675

Gnomad4 NFE exome AF: 0.00764

Gnomad4 OTH exome AF: 0.00456

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

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00565

Gnomad4 NFE AF: 0.00628

Gnomad4 OTH AF: 0.00425

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:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	CASQ2: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2016	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. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 28, 2014	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. -

Catecholaminergic polymorphic ventricular tachycardia 2 Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 17, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 07, 2022	- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2013

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

Benign, criteria provided, single submitter

clinical testing

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

Nov 17, 2017

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Primary dilated cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs397516641; hg19: chr1-116243874;