1-115738349-C-T

Variant names:

• chr1-115738349-C-T
• rs139281637
• NM_001232.4:c.421-14G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001232.4(CASQ2):​c.421-14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,422,228 control chromosomes in the GnomAD database, including 2 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 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: CASQ2 NM_001232.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.676
• Publications: 1 publications found

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]

CASQ2 Gene-Disease associations (from GenCC):

• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• catecholaminergic polymorphic ventricular tachycardia 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Genomics England PanelApp
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-115738349-C-T is Benign according to our data. Variant chr1-115738349-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44164.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00109 (166/152312) while in subpopulation NFE AF = 0.00201 (137/68030). AF 95% confidence interval is 0.00174. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.421-14G>A		intron_variant	Intron 3 of 10	ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.421-14G>A		intron_variant	Intron 3 of 10	1	NM_001232.4	ENSP00000261448.5

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00111 AC: 280 AN: 251204 AF XY: 0.00103

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00190

Gnomad NFE exome AF: 0.00194

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00155 AC: 1964 AN: 1269916 Hom.: 2 Cov.: 20 AF XY: 0.00148 AC XY: 948 AN XY: 642158

African (AFR) AF: 0.000338 AC: 10 AN: 29624

American (AMR) AF: 0.000247 AC: 11 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.0000400 AC: 1 AN: 24992

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38848

South Asian (SAS) AF: 0.0000486 AC: 4 AN: 82380

European-Finnish (FIN) AF: 0.00235 AC: 125 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5390

European-Non Finnish (NFE) AF: 0.00188 AC: 1759 AN: 936980

Other (OTH) AF: 0.000981 AC: 53 AN: 54018

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000953 AC XY: 71 AN XY: 74480

African (AFR) AF: 0.000337 AC: 14 AN: 41570

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00201 AC: 137 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.000835

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

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 01, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The c.421-14G>A var iant in CASQ2 has been reported in 6 individuals with different cardiomyopathies (HCM, DCM, LVNC, CPVT), two of whom also carried another variant sufficient to explain disease (Laitinen 2003, LMM data). This variant has been identified in 0 .2% (123/66738) of European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org. dbSNP rs139281637). This variant is located i n the 3' splice region. Computational tools do not suggest an impact to splicing . However, this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the c.421-14G>A variant is uncert ain, these data suggest that it is more likely to be benign.

Nov 18, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

May 12, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CASQ2 c.421-14G>A alters a nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 251204 control chromosomes, predominantly at a frequency of 0.0019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CASQ2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (0.0016). c.421-14G>A has been observed in at least one individual affected with Catecholaminergic Polymorphic Ventricular Tachycardia, without strong evidence for causality and in a child with hypertrophic cardiomyopathy who had a co-occurring pathogenic variant reported in MYH7 (Laitinen_2003, Burstein_2021). These reports do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32746448, 14571276). ClinVar contains an entry for this variant (Variation ID: 44164). Based on the evidence outlined above, the variant was classified as benign.

Catecholaminergic polymorphic ventricular tachycardia 2 Uncertain:1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CASQ2-related disorder Benign:1

May 03, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		0.68
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

Other links and lift over

dbSNP: rs139281637; hg19: chr1-116280970;