rs28730711

Positions:

• chr1-115701247-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001232.4(CASQ2):​c.1194T>C​(p.Asp398=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0561 in 1,612,070 control chromosomes in the GnomAD database, including 2,957 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (272 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2685 hom.)
• Consequence: CASQ2 NM_001232.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.757

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-115701247-A-G is Benign according to our data. Variant chr1-115701247-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 44159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115701247-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.757 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.1194T>C	p.Asp398=	synonymous_variant	11/11	ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.1194T>C	p.Asp398=	synonymous_variant	11/11	1	NM_001232.4	ENSP00000261448	P1
CASQ2	ENST00000488931.2	c.*566T>C		3_prime_UTR_variant, NMD_transcript_variant	13/13	3		ENSP00000518226

Frequencies

GnomAD3 genomes AF: 0.0484 AC: 7367 AN: 152080 Hom.: 272 Cov.: 32

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.0960

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0386

Gnomad FIN AF: 0.0435

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0633

Gnomad OTH AF: 0.0603

GnomAD3 exomes AF: 0.0566 AC: 14218 AN: 251300 Hom.: 542 AF XY: 0.0563 AC XY: 7643 AN XY: 135824

Gnomad AFR exome AF: 0.00966

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.0604

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0447

Gnomad FIN exome AF: 0.0464

Gnomad NFE exome AF: 0.0630

Gnomad OTH exome AF: 0.0541

GnomAD4 exome AF: 0.0569 AC: 83038 AN: 1459872 Hom.: 2685 Cov.: 30 AF XY: 0.0570 AC XY: 41397 AN XY: 726418

Gnomad4 AFR exome AF: 0.00922

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.0636

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0466

Gnomad4 FIN exome AF: 0.0484

Gnomad4 NFE exome AF: 0.0599

Gnomad4 OTH exome AF: 0.0526

GnomAD4 genome AF: 0.0484 AC: 7369 AN: 152198 Hom.: 272 Cov.: 32 AF XY: 0.0489 AC XY: 3636 AN XY: 74412

Gnomad4 AFR AF: 0.0113

Gnomad4 AMR AF: 0.0958

Gnomad4 ASJ AF: 0.0620

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0389

Gnomad4 FIN AF: 0.0435

Gnomad4 NFE AF: 0.0633

Gnomad4 OTH AF: 0.0597

Alfa AF: 0.0577 Hom.: 173

Bravo AF: 0.0492

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.0661

EpiControl AF: 0.0625

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Nov 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 16, 2011	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Catecholaminergic polymorphic ventricular tachycardia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Caudal regression sequence Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Neural tube defect Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2015

This alteration is classified as 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
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.50
DANN	Benign	0.71

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: rs28730711; hg19: chr1-116243868; COSMIC: COSV54768379; COSMIC: COSV54768379;