rs397516639

Positions:

• chr1-115701350-T-TC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The ENST00000261448.6(CASQ2):​c.1090_1091insG​(p.Asp364GlyfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,316 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D364D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CASQ2 ENST00000261448.6 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.42

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0917 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.1090_1091insG	p.Asp364GlyfsTer10	frameshift_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.1090_1091insG	p.Asp364GlyfsTer10	frameshift_variant	11/11	1	NM_001232.4	ENSP00000261448	P1
CASQ2	ENST00000488931.2	c.*462_*463insG		3_prime_UTR_variant, NMD_transcript_variant	13/13	3		ENSP00000518226

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461316 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727008

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 02, 2012

Variant classified as Uncertain Significance - Favor Pathogenic. The Asp364fs va riant (CASQ2) has not been reported in the literature nor previously identified by our laboratory. This frameshift variant is predicted to alter the protein?s a mino acid sequence beginning at position 364 and lead to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. The role of loss of function variants in CASQ2 in cardiomyopathy remains unclear. A different frameshift variant was reported in i ndividuals with CPVT (di Barletta 2006). Individuals with clinical features of C PVT carried this variant in a homozygous state or as a compound heterozygote wit h another CASQ2 variant. Heterozygous carriers of the frameshift variant did not have features of CPVT, suggesting that cardiomyopathy related to this gene may be inherited in a recessive form. However, more information is needed to fully a ssess the inheritance of this gene in CPVT, as well as its role in other cardiom yopathies. In summary, the Asp364fs variant is likely to be pathogenic in recess ive CPVT, though segregation studies and functional analyses are required to ful ly establish the pathogenicity of this variant. -

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: rs397516639; hg19: chr1-116243971;