1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAA

Variant names:

• chr1-115725557-G-GA
• rs56889721
• NM_001232.4:c.738-5dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001232.4(CASQ2):​c.738-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (319 hom., cov: 0)
  • Exomes 𝑓: 0.035 (79 hom.)
• Consequence: CASQ2 NM_001232.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.516
• 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: 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 -16 ACMG points.

• BP6: Variant 1-115725557-G-GA is Benign according to our data. Variant chr1-115725557-G-GA is described in ClinVar as Benign. ClinVar VariationId is 915585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 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.738-5dupT		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.738-5_738-4insT		splice_region intron	N/A	ENSP00000261448.5	O14958-1
	CASQ2	ENST00000713711.1		c.879-5_879-4insT		splice_region intron	N/A	ENSP00000519014.1	A0AAQ5BGS1
	CASQ2	ENST00000874189.1		c.738-5_738-4insT		splice_region intron	N/A	ENSP00000544248.1

Frequencies

GnomAD3 genomes AF: 0.0521 AC: 5925 AN: 113780 Hom.: 319 Cov.: 0

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0901

Gnomad ASJ AF: 0.000669

Gnomad EAS AF: 0.0643

Gnomad SAS AF: 0.00700

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.0395

GnomAD4 exome AF: 0.0349 AC: 44129 AN: 1264726 Hom.: 79 Cov.: 0 AF XY: 0.0348 AC XY: 21900 AN XY: 629560

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

African (AFR) AF: 0.0787 AC: 2159 AN: 27440

American (AMR) AF: 0.0736 AC: 2252 AN: 30604

Ashkenazi Jewish (ASJ) AF: 0.0475 AC: 1055 AN: 22194

East Asian (EAS) AF: 0.0409 AC: 1447 AN: 35358

South Asian (SAS) AF: 0.0463 AC: 3256 AN: 70294

European-Finnish (FIN) AF: 0.0379 AC: 1374 AN: 36218

Middle Eastern (MID) AF: 0.0239 AC: 87 AN: 3636

European-Non Finnish (NFE) AF: 0.0311 AC: 30645 AN: 986638

Other (OTH) AF: 0.0354 AC: 1854 AN: 52344

⚠️ 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: 0.0521 AC: 5930 AN: 113752 Hom.: 319 Cov.: 0 AF XY: 0.0541 AC XY: 2854 AN XY: 52764

African (AFR) AF: 0.145 AC: 4466 AN: 30700

American (AMR) AF: 0.0901 AC: 925 AN: 10264

Ashkenazi Jewish (ASJ) AF: 0.000669 AC: 2 AN: 2990

East Asian (EAS) AF: 0.0642 AC: 244 AN: 3800

South Asian (SAS) AF: 0.00675 AC: 22 AN: 3260

European-Finnish (FIN) AF: 0.0179 AC: 63 AN: 3524

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

European-Non Finnish (NFE) AF: 0.00259 AC: 147 AN: 56676

Other (OTH) AF: 0.0395 AC: 61 AN: 1546

Alfa AF: 0.0485 Hom.: 284

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiomyopathy (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1;C2677794:Catecholaminergic polymorphic ventricular tachycardia 2 (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 2 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.52
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: rs56889721; hg19: chr1-116268178; COSMIC: COSV105844815; COSMIC: COSV105844815;