1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001232.4(CASQ2):​c.738-5delT 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 0.028 (51 hom., cov: 0)
  • Exomes 𝑓: 0.13 (14 hom.)
• Consequence: CASQ2 NM_001232.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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-GA-G is Benign according to our data. Variant chr1-115725557-GA-G is described in ClinVar as Benign. ClinVar VariationId is 522226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0284 (3235/113944) while in subpopulation AFR AF = 0.0456 (1407/30828). AF 95% confidence interval is 0.0437. There are 51 homozygotes in GnomAd4. There are 1486 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 AR,AD gene

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

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 3233 AN: 113974 Hom.: 51 Cov.: 0

Gnomad AFR AF: 0.0456

Gnomad AMI AF: 0.00260

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.00669

Gnomad EAS AF: 0.00523

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.00624

Gnomad MID AF: 0.0122

Gnomad NFE AF: 0.0260

Gnomad OTH AF: 0.0227

GnomAD4 exome AF: 0.132 AC: 164324 AN: 1244766 Hom.: 14 Cov.: 0 AF XY: 0.128 AC XY: 79523 AN XY: 619174

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

African (AFR) AF: 0.0884 AC: 2424 AN: 27410

American (AMR) AF: 0.0762 AC: 2344 AN: 30744

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2476 AN: 21822

East Asian (EAS) AF: 0.0952 AC: 3352 AN: 35192

South Asian (SAS) AF: 0.0885 AC: 6105 AN: 68948

European-Finnish (FIN) AF: 0.104 AC: 3738 AN: 35852

Middle Eastern (MID) AF: 0.120 AC: 429 AN: 3566

European-Non Finnish (NFE) AF: 0.141 AC: 136614 AN: 969550

Other (OTH) AF: 0.132 AC: 6842 AN: 51682

⚠️ 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: 0.0284 AC: 3235 AN: 113944 Hom.: 51 Cov.: 0 AF XY: 0.0281 AC XY: 1486 AN XY: 52850

African (AFR) AF: 0.0456 AC: 1407 AN: 30828

American (AMR) AF: 0.0215 AC: 221 AN: 10300

Ashkenazi Jewish (ASJ) AF: 0.00669 AC: 20 AN: 2990

East Asian (EAS) AF: 0.00525 AC: 20 AN: 3812

South Asian (SAS) AF: 0.00951 AC: 31 AN: 3260

European-Finnish (FIN) AF: 0.00624 AC: 22 AN: 3526

Middle Eastern (MID) AF: 0.0134 AC: 3 AN: 224

European-Non Finnish (NFE) AF: 0.0260 AC: 1474 AN: 56690

Other (OTH) AF: 0.0226 AC: 35 AN: 1546

Alfa AF: 0.0322 Hom.: 284

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 2 (2)
-	-	1	Cardiomyopathy (1)
-	-	1	CASQ2-related disorder (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		=99/1	polymorphism

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;