NM_001232.4:c.839-2699G>A

Variant names:

• chr1-115707991-C-T
• rs6684209
• NM_001232.4:c.839-2699G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001232.4(CASQ2):​c.839-2699G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 152,074 control chromosomes in the GnomAD database, including 2,250 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2250 hom., cov: 32)
• Consequence: CASQ2 NM_001232.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.326
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.839-2699G>A		intron_variant	Intron 8 of 10	ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.839-2699G>A		intron_variant	Intron 8 of 10	1	NM_001232.4	ENSP00000261448.5

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25605 AN: 151954 Hom.: 2250 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.151

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.168 AC: 25612 AN: 152074 Hom.: 2250 Cov.: 32 AF XY: 0.170 AC XY: 12623 AN XY: 74340

African (AFR) AF: 0.139 AC: 5769 AN: 41492

American (AMR) AF: 0.193 AC: 2956 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 391 AN: 3466

East Asian (EAS) AF: 0.248 AC: 1279 AN: 5158

South Asian (SAS) AF: 0.169 AC: 816 AN: 4822

European-Finnish (FIN) AF: 0.189 AC: 1989 AN: 10548

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11902 AN: 67990

Other (OTH) AF: 0.149 AC: 315 AN: 2110

Alfa AF: 0.176 Hom.: 5281

Bravo AF: 0.170

Asia WGS AF: 0.171 AC: 596 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.6
DANN	Benign	0.36
PhyloP100		0.33
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6684209; hg19: chr1-116250612; COSMIC: COSV54768798;