1-115700223-ATTT-ATTTT

Variant names:

• chr1-115700223-A-AT
• rs11347859
• NM_001232.4:c.*1017dupA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_001232.4(CASQ2):​c.*1017dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0025 (0 hom.)
• Consequence: CASQ2 NM_001232.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.400
• Publications: 0 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 -1 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00186 (276/148044) while in subpopulation AFR AF = 0.00274 (111/40442). AF 95% confidence interval is 0.00233. There are 1 homozygotes in GnomAd4. There are 138 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*1017dupA		3_prime_UTR	Exon 11 of 11	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.*1017dupA		3_prime_UTR	Exon 11 of 11	ENSP00000261448.5	O14958-1
	CASQ2	ENST00000713711.1		c.*1017dupA		3_prime_UTR	Exon 12 of 12	ENSP00000519014.1	A0AAQ5BGS1
	CASQ2	ENST00000874189.1		c.*1017dupA		3_prime_UTR	Exon 10 of 10	ENSP00000544248.1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 273 AN: 147962 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000735

Gnomad ASJ AF: 0.00935

Gnomad EAS AF: 0.000989

Gnomad SAS AF: 0.00149

Gnomad FIN AF: 0.00167

Gnomad MID AF: 0.00658

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00196

GnomAD4 exome AF: 0.00251 AC: 1 AN: 398 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 240

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00255 AC: 1 AN: 392

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

⚠️ 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: 0.00186 AC: 276 AN: 148044 Hom.: 1 Cov.: 0 AF XY: 0.00191 AC XY: 138 AN XY: 72098

African (AFR) AF: 0.00274 AC: 111 AN: 40442

American (AMR) AF: 0.000735 AC: 11 AN: 14974

Ashkenazi Jewish (ASJ) AF: 0.00935 AC: 32 AN: 3422

East Asian (EAS) AF: 0.000992 AC: 5 AN: 5040

South Asian (SAS) AF: 0.00149 AC: 7 AN: 4700

European-Finnish (FIN) AF: 0.00167 AC: 16 AN: 9598

Middle Eastern (MID) AF: 0.00709 AC: 2 AN: 282

European-Non Finnish (NFE) AF: 0.00132 AC: 88 AN: 66618

Other (OTH) AF: 0.00194 AC: 4 AN: 2060

Alfa AF: 0.00 Hom.: 193

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Catecholaminergic polymorphic ventricular tachycardia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.40
Mutation Taster		=100/0	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: rs11347859; hg19: chr1-116242844;