chr1-115740722-A-G

Variant names:

• chr1-115740722-A-G
• rs9428083
• NM_001232.4:c.420+6T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001232.4(CASQ2):​c.420+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.834 in 1,571,264 control chromosomes in the GnomAD database, including 558,295 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (42138 hom., cov: 30)
  • Exomes 𝑓: 0.85 (516157 hom.)
• Consequence: CASQ2 NM_001232.4 splice_region, intron
• Scores: Splicing: ADA: 0.01831
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.489

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-115740722-A-G is Benign according to our data. Variant chr1-115740722-A-G is described in ClinVar as [Benign]. Clinvar id is 44163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115740722-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.420+6T>C		splice_region_variant, intron_variant	Intron 3 of 10	ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.420+6T>C		splice_region_variant, intron_variant	Intron 3 of 10	1	NM_001232.4	ENSP00000261448.5
CASQ2	ENST00000488931.2	n.144+6T>C		splice_region_variant, intron_variant	Intron 4 of 12	3		ENSP00000518226.1

Frequencies

GnomAD3 genomes AF: 0.711 AC: 108052 AN: 151940 Hom.: 42127 Cov.: 30

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.967

Gnomad AMR AF: 0.763

Gnomad ASJ AF: 0.856

Gnomad EAS AF: 0.762

Gnomad SAS AF: 0.740

Gnomad FIN AF: 0.817

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.875

Gnomad OTH AF: 0.747

GnomAD3 exomes AF: 0.796 AC: 199565 AN: 250784 Hom.: 81593 AF XY: 0.806 AC XY: 109246 AN XY: 135562

Gnomad AFR exome AF: 0.352

Gnomad AMR exome AF: 0.774

Gnomad ASJ exome AF: 0.846

Gnomad EAS exome AF: 0.770

Gnomad SAS exome AF: 0.746

Gnomad FIN exome AF: 0.813

Gnomad NFE exome AF: 0.875

Gnomad OTH exome AF: 0.817

GnomAD4 exome AF: 0.847 AC: 1202361 AN: 1419206 Hom.: 516157 Cov.: 24 AF XY: 0.846 AC XY: 599726 AN XY: 708736

Gnomad4 AFR exome AF: 0.344

Gnomad4 AMR exome AF: 0.774

Gnomad4 ASJ exome AF: 0.845

Gnomad4 EAS exome AF: 0.678

Gnomad4 SAS exome AF: 0.750

Gnomad4 FIN exome AF: 0.814

Gnomad4 NFE exome AF: 0.883

Gnomad4 OTH exome AF: 0.820

GnomAD4 genome AF: 0.711 AC: 108081 AN: 152058 Hom.: 42138 Cov.: 30 AF XY: 0.711 AC XY: 52849 AN XY: 74322

Gnomad4 AFR AF: 0.365

Gnomad4 AMR AF: 0.764

Gnomad4 ASJ AF: 0.856

Gnomad4 EAS AF: 0.762

Gnomad4 SAS AF: 0.740

Gnomad4 FIN AF: 0.817

Gnomad4 NFE AF: 0.875

Gnomad4 OTH AF: 0.750

Alfa AF: 0.843 Hom.: 107312

Bravo AF: 0.695

Asia WGS AF: 0.703 AC: 2443 AN: 3476

EpiCase AF: 0.872

EpiControl AF: 0.874

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 2 Benign:5

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Sep 16, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Catecholaminergic polymorphic ventricular tachycardia Benign:1

Sep 23, 2022

Cohesion Phenomics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.8
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.018
dbscSNV1_RF	Benign	0.076
SpliceAI score (max)		0.020		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: rs9428083; hg19: chr1-116283343; COSMIC: COSV54768907;