rs72554070

chr1-115701244-TTCA-Tchr1-115701244-TTCA-TTCATCAchr1-115701244-TTCA-TTCATCATCA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001232.4(CASQ2):c.1194_1196del(p.Asp398del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. D398D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CASQ2 NM_001232.4 inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 1.62

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 Likely_benign. Variant got -2 ACMG points.

• BP6: Variant 1-115701244-TTCA-T is Benign according to our data. Variant chr1-115701244-TTCA-T is described in ClinVar as [Likely_benign]. Clinvar id is 190752.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115701244-TTCA-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASQ2	NM_001232.4	c.1194_1196del	p.Asp398del	inframe_deletion	11/11	ENST00000261448.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASQ2	ENST00000261448.6	c.1194_1196del	p.Asp398del	inframe_deletion	11/11	1	NM_001232.4	P1
CASQ2	ENST00000488931.2	c.*566_*568del		3_prime_UTR_variant, NMD_transcript_variant	13/13	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460402 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726626

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 14, 2011	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below, we initially classified it as a VUS. However, we now believe it is a VUS that is probably benign based on new data from ExAC (see below). p.Asp398del has not been reported as a disease-causing variant, and it is not present in HGMD as of August 2014. It has previously been reported in two families with left ventricular non-compaction (LVNC) by Hoegemaekers et al. (2010); however, the variant did not co-segregate with disease in either family. This variant has also been detected in a 5-year-old girl with bradycardia, exercise-induced arrhythmias including bidirectional VT (consistent with CPVT) and a heavily trabeculated LV—but the patient also reportedly had an R169Q variant in the RYR2 gene and a K4455R variant in the TTN gene (Egan et al. 2013). This variant involves an in-frame deletion of an aspartic acid that is part of a string of 5 negatively-charged aspartic acid residues at the C-terminal end of the protein. These aspartic acid residues vary somewhat across vertebrate species. Deletion of one of these C-terminal aspartic acids has not been reported in ~6000 individuals from publicly available population datasets. It is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4100 Caucasian and ~1800 African American individuals. The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is no deletion of this amino acid listed in 1000 Genomes (as of November 3, 2014). An updated assessment on 10/5/2015 found that variation at this codon has been seen frequently in the ExAC dataset. It is most common in Caucasians: 598 Caucasians in ExAC have this variant, and 5 of them are homozygotes. It is also found in 28 African, 16 Latino, 16 South Asian, 1 East Asian, and 1 "other" for a total allele frequency of 0.5% overall and 0.8% in Caucasians. ExAC contains ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 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. -

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: rs72554070; hg19: chr1-116243865;