1-115701291-TATCATC-TATC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS1

The NM_001232.4(CASQ2):c.1147_1149del(p.Asp383del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,590,878 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00027 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 1 hom. )

Consequence

CASQ2
NM_001232.4 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 7.20

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 -5 ACMG points.

BP6

Variant 1-115701291-TATC-T is Benign according to our data. Variant chr1-115701291-TATC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44155.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}. Variant chr1-115701291-TATC-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000269 (41/152202) while in subpopulation SAS AF= 0.00145 (7/4828). AF 95% confidence interval is 0.00068. There are 2 homozygotes in gnomad4. There are 18 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	UniProt
CASQ2	NM_001232.4 linkuse as main transcript	c.1147_1149del	p.Asp383del	inframe_deletion	11/11	ENST00000261448.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASQ2	ENST00000261448.6 linkuse as main transcript	c.1147_1149del	p.Asp383del	inframe_deletion	11/11	1	NM_001232.4	P1	O14958-1
CASQ2	ENST00000488931.2 linkuse as main transcript	c.519_521del		3_prime_UTR_variant, NMD_transcript_variant	13/13	3

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000284

AC:

AN:

250136

Hom.:

AF XY:

0.000259

AC XY:

AN XY:

135164

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.000525

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000319

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000359

AC:

516

AN:

1438676

Hom.:

AF XY:

0.000367

AC XY:

263

AN XY:

717050

show subpopulations

Gnomad4 AFR exome

AF:

0.000879

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000657

Gnomad4 SAS exome

AF:

0.000514

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000330

Gnomad4 OTH exome

AF:

0.000722

GnomAD4 genome

AF:

0.000269

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000272

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 26, 2021	Thep.Asp378[5] variant in CASQ2 is classified as likely benign because it has been identified in 0.05% (16/30482) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is a deletion of one amino acid at position 383 which occurs within a repetitive region of 6 amino acids and is not predicted to alter the protein reading-frame. ACMG/AMP Criteria applied: BS1, BP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 04, 2016	- -

Catecholaminergic polymorphic ventricular tachycardia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 23, 2016

- -

Catecholaminergic polymorphic ventricular tachycardia 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

May 19, 2023

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2022

This variant, c.1147_1149del, results in the deletion of 1 amino acid(s) of the CASQ2 protein (p.Asp383del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 44155). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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.

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