chr1-115701103-A-G

Position:

• chr1-115701103-A-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.*138T>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 0.0778 in 1,316,914 control chromosomes in the GnomAD database, including 4,750 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1004 hom., cov: 32)
  • Exomes 𝑓: 0.074 (3746 hom.)
• Consequence: CASQ2 NM_001232.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.485

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=-0.82).
• BP6: Variant 1-115701103-A-G is Benign according to our data. Variant chr1-115701103-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 292124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASQ2	NM_001232.4	c.*138T>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.*138T>C		3_prime_UTR_variant	11/11	1	NM_001232.4	P1
CASQ2	ENST00000488931.2	c.*710T>C		3_prime_UTR_variant, NMD_transcript_variant	13/13	3

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15698 AN: 152056 Hom.: 1002 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0594

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.0999

Gnomad SAS AF: 0.0391

Gnomad FIN AF: 0.0944

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0754

Gnomad OTH AF: 0.100

GnomAD4 exome AF: 0.0745 AC: 86767 AN: 1164738 Hom.: 3746 Cov.: 16 AF XY: 0.0734 AC XY: 43567 AN XY: 593328

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.0371

Gnomad4 ASJ exome AF: 0.0984

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.0393

Gnomad4 FIN exome AF: 0.0886

Gnomad4 NFE exome AF: 0.0721

Gnomad4 OTH exome AF: 0.0809

GnomAD4 genome AF: 0.103 AC: 15712 AN: 152176 Hom.: 1004 Cov.: 32 AF XY: 0.103 AC XY: 7636 AN XY: 74396

Gnomad4 AFR AF: 0.176

Gnomad4 AMR AF: 0.0594

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.0997

Gnomad4 SAS AF: 0.0391

Gnomad4 FIN AF: 0.0944

Gnomad4 NFE AF: 0.0754

Gnomad4 OTH AF: 0.0989

Alfa AF: 0.0849 Hom.: 129

Bravo AF: 0.102

Asia WGS AF: 0.0730 AC: 257 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
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. -

Catecholaminergic polymorphic ventricular tachycardia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Caudal regression sequence Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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	-0.82
CADD	Benign	5.0
DANN	Benign	0.61

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: rs28730710; hg19: chr1-116243724;