1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAAA

Variant names:

• chr1-115725557-GAAAAAA-G
• rs56889721
• NM_001232.4:c.738-10_738-5delTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_001232.4(CASQ2):​c.738-10_738-5delTTTTTT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00124 in 1,399,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: CASQ2 NM_001232.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 1-115725557-GAAAAAA-G is Benign according to our data. Variant chr1-115725557-GAAAAAA-G is described in ClinVar as Benign. ClinVar VariationId is 917550.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000623 (71/114000) while in subpopulation NFE AF = 0.000952 (54/56720). AF 95% confidence interval is 0.000749. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.738-10_738-5delTTTTTT		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.738-10_738-5delTTTTTT		splice_region intron	N/A	ENSP00000261448.5	O14958-1
	CASQ2	ENST00000713711.1		c.879-10_879-5delTTTTTT		splice_region intron	N/A	ENSP00000519014.1	A0AAQ5BGS1
	CASQ2	ENST00000874189.1		c.738-10_738-5delTTTTTT		splice_region intron	N/A	ENSP00000544248.1

Frequencies

GnomAD3 genomes AF: 0.000623 AC: 71 AN: 114030 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000390

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000388

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: 0.000952

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00130 AC: 1671 AN: 1285780 Hom.: 0 AF XY: 0.00124 AC XY: 795 AN XY: 640494

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

African (AFR) AF: 0.00156 AC: 44 AN: 28282

American (AMR) AF: 0.00132 AC: 42 AN: 31746

Ashkenazi Jewish (ASJ) AF: 0.000440 AC: 10 AN: 22710

East Asian (EAS) AF: 0.000770 AC: 28 AN: 36358

South Asian (SAS) AF: 0.000372 AC: 27 AN: 72610

European-Finnish (FIN) AF: 0.00167 AC: 62 AN: 37060

Middle Eastern (MID) AF: 0.000818 AC: 3 AN: 3668

European-Non Finnish (NFE) AF: 0.00138 AC: 1384 AN: 999998

Other (OTH) AF: 0.00133 AC: 71 AN: 53348

⚠️ 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: 0.000623 AC: 71 AN: 114000 Hom.: 0 Cov.: 0 AF XY: 0.000586 AC XY: 31 AN XY: 52882

African (AFR) AF: 0.000389 AC: 12 AN: 30842

American (AMR) AF: 0.000388 AC: 4 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: 0.000952 AC: 54 AN: 56720

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

Alfa AF: 0.000917 Hom.: 284

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1
Mutation Taster		=68/32	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs56889721; hg19: chr1-116268178;