chr1-115700738-C-T

Position:

• chr1-115700738-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001232.4(CASQ2):​c.*503G>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 0.00397 in 401,288 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (4 hom.)
• Consequence: CASQ2 NM_001232.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.463

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00364 (554/152310) while in subpopulation NFE AF= 0.00535 (364/68026). AF 95% confidence interval is 0.0049. There are 2 homozygotes in gnomad4. There are 262 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASQ2	NM_001232.4	c.*503G>A		3_prime_UTR_variant	11/11	ENST00000261448.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASQ2	ENST00000261448.6	c.*503G>A		3_prime_UTR_variant	11/11	1	NM_001232.4	P1
CASQ2	ENST00000488931.2	c.*1075G>A		3_prime_UTR_variant, NMD_transcript_variant	13/13	3

Frequencies

GnomAD3 genomes AF: 0.00364 AC: 554 AN: 152192 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00593

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00535

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.00417 AC: 1039 AN: 248978 Hom.: 4 Cov.: 0 AF XY: 0.00407 AC XY: 513 AN XY: 126046

Gnomad4 AFR exome AF: 0.000755

Gnomad4 AMR exome AF: 0.00446

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00721

Gnomad4 NFE exome AF: 0.00508

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.00364 AC: 554 AN: 152310 Hom.: 2 Cov.: 32 AF XY: 0.00352 AC XY: 262 AN XY: 74488

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00593

Gnomad4 NFE AF: 0.00535

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00418 Hom.: 0

Bravo AF: 0.00380

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 2 Uncertain:2

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Catecholaminergic polymorphic ventricular tachycardia 1;C2677794:Catecholaminergic polymorphic ventricular tachycardia 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.6
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: rs72554068; hg19: chr1-116243359;