chr1-115700609-C-G

Position:

• chr1-115700609-C-G

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.*632G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.65 in 170,186 control chromosomes in the GnomAD database, including 36,907 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33469 hom., cov: 32)
  • Exomes 𝑓: 0.60 (3438 hom.)
• Consequence: CASQ2 NM_001232.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:4
• Conservation: PhyloP100: -0.401

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=-0.93).
• BP6: Variant 1-115700609-C-G is Benign according to our data. Variant chr1-115700609-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 292120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASQ2	NM_001232.4	c.*632G>C		3_prime_UTR_variant	11/11	ENST00000261448.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASQ2	ENST00000261448.6	c.*632G>C		3_prime_UTR_variant	11/11	1	NM_001232.4	P1
CASQ2	ENST00000488931.2	c.*1204G>C		3_prime_UTR_variant, NMD_transcript_variant	13/13	3

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99678 AN: 151890 Hom.: 33419 Cov.: 32

Gnomad AFR AF: 0.782

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.685

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.709

Gnomad SAS AF: 0.645

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.661

GnomAD4 exome AF: 0.598 AC: 10877 AN: 18178 Hom.: 3438 Cov.: 0 AF XY: 0.601 AC XY: 5564 AN XY: 9260

Gnomad4 AFR exome AF: 0.783

Gnomad4 AMR exome AF: 0.726

Gnomad4 ASJ exome AF: 0.541

Gnomad4 EAS exome AF: 0.665

Gnomad4 SAS exome AF: 0.607

Gnomad4 FIN exome AF: 0.559

Gnomad4 NFE exome AF: 0.553

Gnomad4 OTH exome AF: 0.595

GnomAD4 genome AF: 0.656 AC: 99786 AN: 152008 Hom.: 33469 Cov.: 32 AF XY: 0.661 AC XY: 49090 AN XY: 74312

Gnomad4 AFR AF: 0.782

Gnomad4 AMR AF: 0.686

Gnomad4 ASJ AF: 0.552

Gnomad4 EAS AF: 0.708

Gnomad4 SAS AF: 0.646

Gnomad4 FIN AF: 0.631

Gnomad4 NFE AF: 0.579

Gnomad4 OTH AF: 0.659

Alfa AF: 0.608 Hom.: 3522

Bravo AF: 0.668

Asia WGS AF: 0.691 AC: 2407 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

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 12, 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

- -

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	-0.93
CADD	Benign	0.28
DANN	Benign	0.42

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: rs1140238; hg19: chr1-116243230;