1-115701098-C-T

Variant names:

• chr1-115701098-C-T
• rs28730709
• NM_001232.4:c.*143G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001232.4(CASQ2):​c.*143G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,282,318 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (75 hom.)
• Consequence: CASQ2 NM_001232.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.558

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-115701098-C-T is Benign according to our data. Variant chr1-115701098-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 368821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.07 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.*143G>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448	c.*143G>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_001232.4	ENSP00000261448.5
CASQ2	ENST00000488931.2	n.*715G>A		non_coding_transcript_exon_variant	Exon 13 of 13	3		ENSP00000518226.1
CASQ2	ENST00000488931.2	n.*715G>A		3_prime_UTR_variant	Exon 13 of 13	3		ENSP00000518226.1

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 436 AN: 152056 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0762

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00228 AC: 2578 AN: 1130144 Hom.: 75 Cov.: 15 AF XY: 0.00220 AC XY: 1268 AN XY: 577362

Gnomad4 AFR exome AF: 0.0000372 AC: 1 AN: 26908

Gnomad4 AMR exome AF: 0.000113 AC: 5 AN: 44064

Gnomad4 ASJ exome AF: 0.000377 AC: 9 AN: 23848

Gnomad4 EAS exome AF: 0.0594 AC: 2264 AN: 38130

Gnomad4 SAS exome AF: 0.000926 AC: 73 AN: 78874

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 49672

Gnomad4 NFE exome AF: 0.0000699 AC: 57 AN: 815514

Gnomad4 Remaining exome AF: 0.00340 AC: 169 AN: 49640

GnomAD4 genome AF: 0.00286 AC: 435 AN: 152174 Hom.: 13 Cov.: 32 AF XY: 0.00297 AC XY: 221 AN XY: 74400

Gnomad4 AFR AF: 0.0000964 AC: 0.0000963577 AN: 0.0000963577

Gnomad4 AMR AF: 0.000851 AC: 0.000850674 AN: 0.000850674

Gnomad4 ASJ AF: 0.000288 AC: 0.000288184 AN: 0.000288184

Gnomad4 EAS AF: 0.0762 AC: 0.076196 AN: 0.076196

Gnomad4 SAS AF: 0.00146 AC: 0.00145833 AN: 0.00145833

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000132 AC: 0.00013233 AN: 0.00013233

Gnomad4 OTH AF: 0.00284 AC: 0.00283822 AN: 0.00283822

Alfa AF: 0.000594 Hom.: 0

Bravo AF: 0.00301

Asia WGS AF: 0.0190 AC: 66 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Caudal regression sequence Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Neural tube defect Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.53
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

Publications

LitVar

Other links and lift over

dbSNP: rs28730709; hg19: chr1-116243719; COSMIC: COSV54770522; COSMIC: COSV54770522;