rs876657635

Positions:

• chr1-115702996-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001232.4(CASQ2):​c.940-1G>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,459,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CASQ2 NM_001232.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.56

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.061666667 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.2, offset of -47, new splice context is: ggcgggtgggtccttaacAGaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-115702996-C-A is Pathogenic according to our data. Variant chr1-115702996-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.940-1G>T		splice_acceptor_variant, intron_variant		ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.940-1G>T		splice_acceptor_variant, intron_variant		1	NM_001232.4	ENSP00000261448.5
CASQ2	ENST00000488931.2	n.*312-1G>T		splice_acceptor_variant, intron_variant		3		ENSP00000518226.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459490 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725822

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 13, 2015

The c.940-1G>T variant in CASQ2 has not been previously reported in individuals with CPVT and was absent from large population studies. This variant occurs in t he invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Homozygous o r compound heterozygous variants in CASQ2 are strongly associated with CPVT and splice variants as well as loss-of-function variants are part of the pathogenic variant spectrum (Roux-Buisson 2011). In summary, although additional studies ar e required to fully establish its clinical significance, the c.940-1G>T variant is likely pathogenic for CPVT in an autosomal recessive manner. -

Catecholaminergic polymorphic ventricular tachycardia 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 14, 2021

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 20, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 228247). This variant has not been reported in the literature in individuals affected with CASQ2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 9 of the CASQ2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CASQ2 are known to be pathogenic (PMID: 12386154). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		6.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.71		Position offset: -22
DS_AL_spliceai		1.0		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876657635; hg19: chr1-116245617;