1-115725557-GAAAAAAAAAAAAAAA-GAAAAAA

Variant names:

• chr1-115725557-GAAAAAAAAA-G
• rs56889721
• NM_001232.4:c.738-13_738-5delTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001232.4(CASQ2):​c.738-13_738-5delTTTTTTTTT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000121 in 1,402,772 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000088 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CASQ2 NM_001232.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.12
• Publications: 3 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: ClinGen, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.738-13_738-5delTTTTTTTTT		splice_region 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.738-13_738-5delTTTTTTTTT		splice_region intron	N/A	ENSP00000261448.5	O14958-1
	CASQ2	ENST00000713711.1		c.879-13_879-5delTTTTTTTTT		splice_region intron	N/A	ENSP00000519014.1	A0AAQ5BGS1
	CASQ2	ENST00000874189.1		c.738-13_738-5delTTTTTTTTT		splice_region intron	N/A	ENSP00000544248.1

Frequencies

GnomAD3 genomes AF: 0.0000877 AC: 10 AN: 114030 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.0000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000194

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00122

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000353

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000124 AC: 160 AN: 1288742 Hom.: 0 AF XY: 0.000120 AC XY: 77 AN XY: 641972

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000740 AC: 21 AN: 28362

American (AMR) AF: 0.0000943 AC: 3 AN: 31828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22772

East Asian (EAS) AF: 0.00 AC: 0 AN: 36486

South Asian (SAS) AF: 0.000632 AC: 46 AN: 72756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37150

Middle Eastern (MID) AF: 0.000272 AC: 1 AN: 3680

European-Non Finnish (NFE) AF: 0.0000838 AC: 84 AN: 1002202

Other (OTH) AF: 0.0000934 AC: 5 AN: 53506

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000877 AC: 10 AN: 114030 Hom.: 1 Cov.: 0 AF XY: 0.0000946 AC XY: 5 AN XY: 52882

African (AFR) AF: 0.0000649 AC: 2 AN: 30806

American (AMR) AF: 0.000194 AC: 2 AN: 10302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2992

East Asian (EAS) AF: 0.00 AC: 0 AN: 3824

South Asian (SAS) AF: 0.00122 AC: 4 AN: 3288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 246

European-Non Finnish (NFE) AF: 0.0000353 AC: 2 AN: 56732

Other (OTH) AF: 0.00 AC: 0 AN: 1544

Alfa AF: 0.00 Hom.: 284

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1
Mutation Taster		=86/14	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs56889721; hg19: chr1-116268178;