NM_001232.4:c.738-7_738-5delTTT

Variant names:

• chr1-115725557-GAAA-G
• rs56889721
• NM_001232.4:c.738-7_738-5delTTT

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.738-7_738-5delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0979 in 1,340,408 control chromosomes in the GnomAD database, including 422 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (412 hom., cov: 0)
  • Exomes 𝑓: 0.10 (10 hom.)
• Consequence: CASQ2 NM_001232.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• 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: 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-GAAA-G is Benign according to our data. Variant chr1-115725557-GAAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 522227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 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.738-7_738-5delTTT		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.738-7_738-5delTTT		splice_region intron	N/A	ENSP00000261448.5	O14958-1
	CASQ2	ENST00000713711.1		c.879-7_879-5delTTT		splice_region intron	N/A	ENSP00000519014.1	A0AAQ5BGS1
	CASQ2	ENST00000874189.1		c.738-7_738-5delTTT		splice_region intron	N/A	ENSP00000544248.1

Frequencies

GnomAD3 genomes AF: 0.0507 AC: 5782 AN: 113970 Hom.: 411 Cov.: 0

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.00501

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.00395

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0163

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.0396

GnomAD4 exome AF: 0.102 AC: 125489 AN: 1226468 Hom.: 10 AF XY: 0.102 AC XY: 62289 AN XY: 609708

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

African (AFR) AF: 0.176 AC: 4740 AN: 26922

American (AMR) AF: 0.0819 AC: 2414 AN: 29492

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2274 AN: 21556

East Asian (EAS) AF: 0.126 AC: 4286 AN: 33890

South Asian (SAS) AF: 0.0873 AC: 5941 AN: 68086

European-Finnish (FIN) AF: 0.104 AC: 3630 AN: 34824

Middle Eastern (MID) AF: 0.139 AC: 484 AN: 3484

European-Non Finnish (NFE) AF: 0.100 AC: 95904 AN: 957432

Other (OTH) AF: 0.115 AC: 5816 AN: 50782

⚠️ 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: 0.0508 AC: 5793 AN: 113940 Hom.: 412 Cov.: 0 AF XY: 0.0517 AC XY: 2731 AN XY: 52840

African (AFR) AF: 0.171 AC: 5263 AN: 30826

American (AMR) AF: 0.0231 AC: 238 AN: 10300

Ashkenazi Jewish (ASJ) AF: 0.00501 AC: 15 AN: 2992

East Asian (EAS) AF: 0.00367 AC: 14 AN: 3814

South Asian (SAS) AF: 0.00399 AC: 13 AN: 3260

European-Finnish (FIN) AF: 0.000283 AC: 1 AN: 3528

Middle Eastern (MID) AF: 0.0179 AC: 4 AN: 224

European-Non Finnish (NFE) AF: 0.00325 AC: 184 AN: 56684

Other (OTH) AF: 0.0395 AC: 61 AN: 1544

Alfa AF: 0.0406 Hom.: 284

ClinVar

ClinVar submissions

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=94/6	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;