1-115731167-A-G

Variant names:

• chr1-115731167-A-G
• rs3010396
• NM_001232.4:c.606+1734T>C

Variant summary

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

The NM_001232.4(CASQ2):​c.606+1734T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 152,036 control chromosomes in the GnomAD database, including 27,129 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 0.59 (27129 hom., cov: 32)
• Consequence: CASQ2 NM_001232.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.268
• Publications: 9 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: AR, AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.691 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASQ2	NM_001232.4	MANE Select	c.606+1734T>C		intron	N/A	NP_001223.2	O14958-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASQ2	ENST00000261448.6	TSL:1 MANE Select	c.606+1734T>C		intron	N/A	ENSP00000261448.5	O14958-1
	CASQ2	ENST00000713711.1		c.747+1734T>C		intron	N/A	ENSP00000519014.1	A0AAQ5BGS1
	CASQ2	ENST00000874189.1		c.606+1734T>C		intron	N/A	ENSP00000544248.1

Frequencies

GnomAD3 genomes AF: 0.592 AC: 89879 AN: 151916 Hom.: 27091 Cov.: 32

Gnomad AFR AF: 0.697

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.599

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

GnomAD4 genome AF: 0.592 AC: 89975 AN: 152036 Hom.: 27129 Cov.: 32 AF XY: 0.594 AC XY: 44134 AN XY: 74294

African (AFR) AF: 0.697 AC: 28918 AN: 41468

American (AMR) AF: 0.597 AC: 9127 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 1698 AN: 3472

East Asian (EAS) AF: 0.647 AC: 3344 AN: 5166

South Asian (SAS) AF: 0.589 AC: 2839 AN: 4822

European-Finnish (FIN) AF: 0.552 AC: 5826 AN: 10546

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.533 AC: 36240 AN: 67968

Other (OTH) AF: 0.598 AC: 1262 AN: 2112

Alfa AF: 0.525 Hom.: 9702

Bravo AF: 0.603

Asia WGS AF: 0.615 AC: 2142 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	5.4
DANN	Benign	0.57
PhyloP100		0.27
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: rs3010396; hg19: chr1-116273788;