1-115717911-A-T

Variant names:

• chr1-115717911-A-T
• rs2997741
• NM_001232.4:c.784-17T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001232.4(CASQ2):​c.784-17T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.565 in 1,569,936 control chromosomes in the GnomAD database, including 252,790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27671 hom., cov: 33)
  • Exomes 𝑓: 0.56 (225119 hom.)
• Consequence: CASQ2 NM_001232.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.349
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• catecholaminergic polymorphic ventricular tachycardia 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Genomics England PanelApp
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-115717911-A-T is Benign according to our data. Variant chr1-115717911-A-T is described in ClinVar as Benign. ClinVar VariationId is 257652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001232.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASQ2	NM_001232.4	MANE Select	c.784-17T>A		intron	N/A	NP_001223.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASQ2	ENST00000261448.6	TSL:1 MANE Select	c.784-17T>A		intron	N/A	ENSP00000261448.5
	CASQ2	ENST00000713711.1		c.925-17T>A		intron	N/A	ENSP00000519014.1
	CASQ2	ENST00000713728.1		c.508-17T>A		intron	N/A	ENSP00000519032.1

Frequencies

GnomAD3 genomes AF: 0.599 AC: 90944 AN: 151924 Hom.: 27632 Cov.: 33

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.625

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.539

Gnomad EAS AF: 0.649

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.601

GnomAD2 exomes AF: 0.580 AC: 145689 AN: 251066 AF XY: 0.575

Gnomad AFR exome AF: 0.696

Gnomad AMR exome AF: 0.627

Gnomad ASJ exome AF: 0.539

Gnomad EAS exome AF: 0.640

Gnomad FIN exome AF: 0.553

Gnomad NFE exome AF: 0.547

Gnomad OTH exome AF: 0.586

GnomAD4 exome AF: 0.562 AC: 796475 AN: 1417894 Hom.: 225119 Cov.: 26 AF XY: 0.561 AC XY: 397419 AN XY: 708204

African (AFR) AF: 0.694 AC: 22618 AN: 32572

American (AMR) AF: 0.624 AC: 27890 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 13822 AN: 25896

East Asian (EAS) AF: 0.671 AC: 26454 AN: 39442

South Asian (SAS) AF: 0.581 AC: 49583 AN: 85398

European-Finnish (FIN) AF: 0.549 AC: 29235 AN: 53286

Middle Eastern (MID) AF: 0.642 AC: 3647 AN: 5680

European-Non Finnish (NFE) AF: 0.550 AC: 589401 AN: 1072054

Other (OTH) AF: 0.574 AC: 33825 AN: 58902

GnomAD4 genome AF: 0.599 AC: 91037 AN: 152042 Hom.: 27671 Cov.: 33 AF XY: 0.601 AC XY: 44686 AN XY: 74312

African (AFR) AF: 0.691 AC: 28673 AN: 41468

American (AMR) AF: 0.608 AC: 9293 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 1871 AN: 3470

East Asian (EAS) AF: 0.649 AC: 3361 AN: 5182

South Asian (SAS) AF: 0.593 AC: 2856 AN: 4820

European-Finnish (FIN) AF: 0.564 AC: 5959 AN: 10558

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.545 AC: 37008 AN: 67948

Other (OTH) AF: 0.600 AC: 1263 AN: 2106

Alfa AF: 0.484 Hom.: 2436

Bravo AF: 0.609

Asia WGS AF: 0.609 AC: 2121 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 2 Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

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:2

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.49
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs2997741; hg19: chr1-116260532; COSMIC: COSV54772132;