1-115700759-G-A

Position:

• chr1-115700759-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001232.4(CASQ2):​c.*482C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 413,770 control chromosomes in the GnomAD database, including 79,849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31288 hom., cov: 32)
  • Exomes 𝑓: 0.60 (48561 hom.)
• Consequence: CASQ2 NM_001232.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.56

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-115700759-G-A is Benign according to our data. Variant chr1-115700759-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 292122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.*482C>T		3_prime_UTR_variant	11/11	ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448	c.*482C>T		3_prime_UTR_variant	11/11	1	NM_001232.4	ENSP00000261448.5
CASQ2	ENST00000488931.2	n.*1054C>T		non_coding_transcript_exon_variant	13/13	3		ENSP00000518226.1
CASQ2	ENST00000488931.2	n.*1054C>T		3_prime_UTR_variant	13/13	3		ENSP00000518226.1

Frequencies

GnomAD3 genomes AF: 0.637 AC: 96777 AN: 151924 Hom.: 31250 Cov.: 32

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.641

Gnomad AMR AF: 0.677

Gnomad ASJ AF: 0.547

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.644

GnomAD4 exome AF: 0.604 AC: 158029 AN: 261728 Hom.: 48561 Cov.: 0 AF XY: 0.602 AC XY: 79887 AN XY: 132728

Gnomad4 AFR exome AF: 0.716

Gnomad4 AMR exome AF: 0.710

Gnomad4 ASJ exome AF: 0.541

Gnomad4 EAS exome AF: 0.717

Gnomad4 SAS exome AF: 0.634

Gnomad4 FIN exome AF: 0.609

Gnomad4 NFE exome AF: 0.576

Gnomad4 OTH exome AF: 0.618

GnomAD4 genome AF: 0.637 AC: 96873 AN: 152042 Hom.: 31288 Cov.: 32 AF XY: 0.642 AC XY: 47707 AN XY: 74284

Gnomad4 AFR AF: 0.718

Gnomad4 AMR AF: 0.677

Gnomad4 ASJ AF: 0.547

Gnomad4 EAS AF: 0.707

Gnomad4 SAS AF: 0.645

Gnomad4 FIN AF: 0.631

Gnomad4 NFE AF: 0.579

Gnomad4 OTH AF: 0.642

Alfa AF: 0.594 Hom.: 54755

Bravo AF: 0.646

Asia WGS AF: 0.684 AC: 2381 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Catecholaminergic polymorphic ventricular tachycardia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Caudal regression sequence Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Neural tube defect Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.32
DANN	Benign	0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs7521023; hg19: chr1-116243380;