rs786205272

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:13

Conservation

PhyloP100: 2.40
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Uncertain_significance=3, Benign=6, Likely_benign=4}. 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 rank MANE Protein UniProt
CASQ2NM_001232.4 linkc.1185_1187delCGA p.Asp396del disruptive_inframe_deletion Exon 11 of 11 ENST00000261448.6 NP_001223.2 O14958-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CASQ2ENST00000261448.6 linkc.1185_1187delCGA p.Asp396del disruptive_inframe_deletion Exon 11 of 11 1 NM_001232.4 ENSP00000261448.5 O14958-1
CASQ2ENST00000488931.2 linkn.*557_*559delCGA non_coding_transcript_exon_variant Exon 13 of 13 3 ENSP00000518226.1
CASQ2ENST00000488931.2 linkn.*557_*559delCGA 3_prime_UTR_variant Exon 13 of 13 3 ENSP00000518226.1

Frequencies

GnomAD3 genomes
AF:
0.00389
AC:
591
AN:
152104
Hom.:
7
Cov.:
31
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:3Benign:13
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:4
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. -

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

- -

-
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

- -

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:4
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. -

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Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

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PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 2 Uncertain:1Benign:2
Dec 17, 2015
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 07, 2022
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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. -

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

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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

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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 v4.3

Name
Calibrated prediction
Score
Prediction

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.

Other links and lift over

dbSNP: rs397516641; hg19: chr1-116243874; API