NM_001232.4:c.738-3C>A

Variant names:

• chr1-115725556-G-T
• rs876657750
• NM_001232.4:c.738-3C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001232.4(CASQ2):​c.738-3C>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000122 in 82,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000012 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CASQ2 NM_001232.4 splice_region, intron
• Scores: Splicing: ADA: 0.1375
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.73
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.738-3C>A		splice_region_variant, intron_variant	Intron 6 of 10	ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.738-3C>A		splice_region_variant, intron_variant	Intron 6 of 10	1	NM_001232.4	ENSP00000261448.5

Frequencies

GnomAD3 genomes AF: 0.0000122 AC: 1 AN: 82260 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000218

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1057282 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 538592

African (AFR) AF: 0.00 AC: 0 AN: 23234

American (AMR) AF: 0.00 AC: 0 AN: 32288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21048

East Asian (EAS) AF: 0.00 AC: 0 AN: 33950

South Asian (SAS) AF: 0.00 AC: 0 AN: 72630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 786668

Other (OTH) AF: 0.00 AC: 0 AN: 44862

GnomAD4 genome AF: 0.0000122 AC: 1 AN: 82260 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 38286

African (AFR) AF: 0.00 AC: 0 AN: 15914

American (AMR) AF: 0.00 AC: 0 AN: 7270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2542

East Asian (EAS) AF: 0.00 AC: 0 AN: 2716

South Asian (SAS) AF: 0.00 AC: 0 AN: 2264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 152

European-Non Finnish (NFE) AF: 0.0000218 AC: 1 AN: 45782

Other (OTH) AF: 0.00 AC: 0 AN: 1054

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 10, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.738-3C>A variant in CASQ2 has not been previously reported in individuals with cardiomyopathy or in large population studies. This variant is located in t he 3' splice region. Computational tools do not suggest an impact to splicing; h owever, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the c.738-3C>A variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	15
DANN	Benign	0.63
PhyloP100		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.14
dbscSNV1_RF	Benign	0.43
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.55		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs876657750; hg19: chr1-116268177;