1-115725557-GAAAAAAAAAAAAAAA-GAAAA

Variant names:

• chr1-115725557-GAAAAAAAAAAA-G
• rs56889721
• NM_001232.4:c.738-15_738-5delTTTTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001232.4(CASQ2):​c.738-15_738-5delTTTTTTTTTTT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000031 in 1,288,842 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: CASQ2 NM_001232.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: 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.

• BP6: Variant 1-115725557-GAAAAAAAAAAA-G is Benign according to our data. Variant chr1-115725557-GAAAAAAAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 2911806.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-GAAAAAAAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 2911806.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-GAAAAAAAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 2911806.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-GAAAAAAAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 2911806.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-GAAAAAAAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 2911806.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-GAAAAAAAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 2911806.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-GAAAAAAAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 2911806.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.738-15_738-5delTTTTTTTTTTT		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.738-15_738-5delTTTTTTTTTTT		splice_region_variant, intron_variant	Intron 6 of 10	1	NM_001232.4	ENSP00000261448.5

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000310 AC: 4 AN: 1288842 Hom.: 0 AF XY: 0.00000156 AC XY: 1 AN XY: 642014

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

African (AFR) AF: 0.0000352 AC: 1 AN: 28378

American (AMR) AF: 0.00 AC: 0 AN: 31834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22774

East Asian (EAS) AF: 0.00 AC: 0 AN: 36490

South Asian (SAS) AF: 0.00 AC: 0 AN: 72760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3680

European-Non Finnish (NFE) AF: 0.00000299 AC: 3 AN: 1002260

Other (OTH) AF: 0.00 AC: 0 AN: 53508

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000233), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

Alfa AF: 0.00 Hom.: 284

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1

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;