rs6684209

Positions:

• chr1-115707991-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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/exons	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.839-2699G>A		intron_variant		ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.839-2699G>A		intron_variant		1	NM_001232.4	ENSP00000261448.5
CASQ2	ENST00000488931.2	n.*211-2699G>A		intron_variant		3		ENSP00000518226.1

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

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.248

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.149

Alfa AF: 0.176 Hom.: 1709

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

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