1-115725557-GAAAAAAAA-G

Variant names:

• chr1-115725557-GAAAAAAAA-G
• rs56889721
• NM_001232.4:c.738-12_738-5delTTTTTTTT

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.738-12_738-5delTTTTTTTT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00105 in 1,402,502 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (8 hom., cov: 0)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: CASQ2 NM_001232.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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: 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-GAAAAAAAA-G is Benign according to our data. Variant chr1-115725557-GAAAAAAAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 695571.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 = 0.00636 (725/114000) while in subpopulation AFR AF = 0.0226 (696/30842). AF 95% confidence interval is 0.0212. There are 8 homozygotes in GnomAd4. There are 334 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.738-12_738-5delTTTTTTTT		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.738-12_738-5delTTTTTTTT		splice_region intron	N/A	ENSP00000261448.5	O14958-1
	CASQ2	ENST00000713711.1		c.879-12_879-5delTTTTTTTT		splice_region intron	N/A	ENSP00000519014.1	A0AAQ5BGS1
	CASQ2	ENST00000874189.1		c.738-12_738-5delTTTTTTTT		splice_region intron	N/A	ENSP00000544248.1

Frequencies

GnomAD3 genomes AF: 0.00636 AC: 725 AN: 114030 Hom.: 8 Cov.: 0

Gnomad AFR AF: 0.0226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00204

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000705

Gnomad OTH AF: 0.00194

GnomAD4 exome AF: 0.000584 AC: 752 AN: 1288502 Hom.: 0 AF XY: 0.000523 AC XY: 336 AN XY: 641840

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

African (AFR) AF: 0.0207 AC: 587 AN: 28324

American (AMR) AF: 0.000628 AC: 20 AN: 31822

Ashkenazi Jewish (ASJ) AF: 0.000132 AC: 3 AN: 22770

East Asian (EAS) AF: 0.000110 AC: 4 AN: 36478

South Asian (SAS) AF: 0.000399 AC: 29 AN: 72740

European-Finnish (FIN) AF: 0.000108 AC: 4 AN: 37140

Middle Eastern (MID) AF: 0.000543 AC: 2 AN: 3680

European-Non Finnish (NFE) AF: 0.0000409 AC: 41 AN: 1002052

Other (OTH) AF: 0.00116 AC: 62 AN: 53496

⚠️ 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: 0.00636 AC: 725 AN: 114000 Hom.: 8 Cov.: 0 AF XY: 0.00632 AC XY: 334 AN XY: 52880

African (AFR) AF: 0.0226 AC: 696 AN: 30842

American (AMR) AF: 0.00204 AC: 21 AN: 10306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2992

East Asian (EAS) AF: 0.00 AC: 0 AN: 3814

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

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

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

European-Non Finnish (NFE) AF: 0.0000705 AC: 4 AN: 56720

Other (OTH) AF: 0.00194 AC: 3 AN: 1546

Alfa AF: 0.00 Hom.: 284

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs56889721; hg19: chr1-116268178;