1-115738350-G-C

Position:

• chr1-115738350-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001232.4(CASQ2):​c.421-15C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000504 in 1,423,534 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (5 hom.)
• Consequence: CASQ2 NM_001232.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.0300

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-115738350-G-C is Benign according to our data. Variant chr1-115738350-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44165.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=2}. Variant chr1-115738350-G-C is described in Lovd as [Benign]. Variant chr1-115738350-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000328 (50/152284) while in subpopulation SAS AF= 0.00311 (15/4822). AF 95% confidence interval is 0.00192. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.421-15C>G		intron_variant		ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.421-15C>G		intron_variant		1	NM_001232.4	ENSP00000261448.5
CASQ2	ENST00000488931.2	n.145-15C>G		intron_variant		3		ENSP00000518226.1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000800 AC: 201 AN: 251126 Hom.: 0 AF XY: 0.00114 AC XY: 155 AN XY: 135758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00510

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000525 AC: 667 AN: 1271250 Hom.: 5 Cov.: 20 AF XY: 0.000703 AC XY: 452 AN XY: 642700

Gnomad4 AFR exome AF: 0.0000337

Gnomad4 AMR exome AF: 0.000225

Gnomad4 ASJ exome AF: 0.000480

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00463

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000222

Gnomad4 OTH exome AF: 0.000703

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74466

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.000227

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 27, 2012	c.421-15C>G in intron 4 of CASQ2: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence and it has been identified in 0.5% (80/16508) of South Asian chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs19993958 2). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 29, 2016	- -

Catecholaminergic polymorphic ventricular tachycardia 2 Uncertain:1 Benign:2

Uncertain significance, 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, 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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Nov 07, 2014	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.51
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs199939582; hg19: chr1-116280971;