1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAAAAA

Variant names:

• chr1-115725557-GAAAA-G
• rs56889721
• NM_001232.4:c.738-8_738-5delTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_001232.4(CASQ2):​c.738-8_738-5delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,370,536 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: CASQ2 NM_001232.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.72
• 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: Benign. The variant received -8 ACMG points.

• BP6: Variant 1-115725557-GAAAA-G is Benign according to our data. Variant chr1-115725557-GAAAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 522228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.738-8_738-5delTTTT		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.738-8_738-5delTTTT		splice_region intron	N/A	ENSP00000261448.5	O14958-1
	CASQ2	ENST00000713711.1		c.879-8_879-5delTTTT		splice_region intron	N/A	ENSP00000519014.1	A0AAQ5BGS1
	CASQ2	ENST00000874189.1		c.738-8_738-5delTTTT		splice_region intron	N/A	ENSP00000544248.1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 15 AN: 114020 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000334

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000567

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000176

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0145 AC: 18204 AN: 1256546 Hom.: 0 AF XY: 0.0143 AC XY: 8959 AN XY: 625266

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

African (AFR) AF: 0.0330 AC: 910 AN: 27588

American (AMR) AF: 0.0176 AC: 539 AN: 30658

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 315 AN: 22216

East Asian (EAS) AF: 0.0239 AC: 832 AN: 34750

South Asian (SAS) AF: 0.0111 AC: 784 AN: 70868

European-Finnish (FIN) AF: 0.0192 AC: 687 AN: 35838

Middle Eastern (MID) AF: 0.0233 AC: 83 AN: 3564

European-Non Finnish (NFE) AF: 0.0134 AC: 13157 AN: 978936

Other (OTH) AF: 0.0172 AC: 897 AN: 52128

⚠️ 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: 0.000132 AC: 15 AN: 113990 Hom.: 0 Cov.: 0 AF XY: 0.000170 AC XY: 9 AN XY: 52880

African (AFR) AF: 0.000357 AC: 11 AN: 30838

American (AMR) AF: 0.00 AC: 0 AN: 10306

Ashkenazi Jewish (ASJ) AF: 0.000334 AC: 1 AN: 2992

East Asian (EAS) AF: 0.00 AC: 0 AN: 3812

South Asian (SAS) AF: 0.00 AC: 0 AN: 3260

European-Finnish (FIN) AF: 0.000567 AC: 2 AN: 3528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 224

European-Non Finnish (NFE) AF: 0.0000176 AC: 1 AN: 56716

Other (OTH) AF: 0.00 AC: 0 AN: 1546

Alfa AF: 0.00 Hom.: 284

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 2 (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56889721; hg19: chr1-116268178;