1-115717911-A-T

Position:

• chr1-115717911-A-T

Variant summary

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

The ENST00000261448.6(CASQ2):​c.784-17T>A variant causes a splice polypyrimidine tract, 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 ENST00000261448.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.349

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=-0.82).
• BP6: Variant 1-115717911-A-T is Benign according to our data. Variant chr1-115717911-A-T is described in ClinVar as [Benign]. Clinvar id is 257652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115717911-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.784-17T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.784-17T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001232.4	ENSP00000261448	P1
CASQ2	ENST00000488931.2	c.*156-17T>A		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		3		ENSP00000518226

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

GnomAD3 exomes AF: 0.580 AC: 145689 AN: 251066 Hom.: 42672 AF XY: 0.575 AC XY: 78076 AN XY: 135676

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 SAS exome AF: 0.585

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

Gnomad4 AFR exome AF: 0.694

Gnomad4 AMR exome AF: 0.624

Gnomad4 ASJ exome AF: 0.534

Gnomad4 EAS exome AF: 0.671

Gnomad4 SAS exome AF: 0.581

Gnomad4 FIN exome AF: 0.549

Gnomad4 NFE exome AF: 0.550

Gnomad4 OTH exome AF: 0.574

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

Gnomad4 AFR AF: 0.691

Gnomad4 AMR AF: 0.608

Gnomad4 ASJ AF: 0.539

Gnomad4 EAS AF: 0.649

Gnomad4 SAS AF: 0.593

Gnomad4 FIN AF: 0.564

Gnomad4 NFE AF: 0.545

Gnomad4 OTH AF: 0.600

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

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

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

Catecholaminergic polymorphic ventricular tachycardia Benign:1

Likely benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.49

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

Publications

LitVar

Other links and lift over

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