rs548536938

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000261448.6(CASQ2):ā€‹c.893A>Gā€‹(p.Asn298Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N298K) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000046 ( 0 hom., cov: 32)
Exomes š‘“: 0.000013 ( 0 hom. )

Consequence

CASQ2
ENST00000261448.6 missense

Scores

10
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.48
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.26986712).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CASQ2NM_001232.4 linkuse as main transcriptc.893A>G p.Asn298Ser missense_variant 9/11 ENST00000261448.6 NP_001223.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CASQ2ENST00000261448.6 linkuse as main transcriptc.893A>G p.Asn298Ser missense_variant 9/111 NM_001232.4 ENSP00000261448 P1O14958-1
CASQ2ENST00000488931.2 linkuse as main transcriptc.*265A>G 3_prime_UTR_variant, NMD_transcript_variant 11/133 ENSP00000518226

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000964
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000438
AC:
11
AN:
251372
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135854
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000435
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461760
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
727182
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000227
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152270
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000966
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
ExAC
AF:
0.0000659
AC:
8
Asia WGS
AF:
0.00144
AC:
5
AN:
3476

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Catecholaminergic polymorphic ventricular tachycardia 1;C2677794:Catecholaminergic polymorphic ventricular tachycardia 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 19, 2021- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 11, 2024In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has been observed in an individual with DCM (PMID: 31983221); This variant is associated with the following publications: (PMID: 31983221) -
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 12, 2022This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 298 of the CASQ2 protein (p.Asn298Ser). This variant is present in population databases (rs548536938, gnomAD 0.02%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 519436). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CASQ2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 27, 2024This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.59
D
Eigen
Benign
0.18
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.97
D
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.27
T
MetaSVM
Benign
-0.39
T
MutationAssessor
Uncertain
2.6
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-3.1
D
REVEL
Uncertain
0.45
Sift
Uncertain
0.017
D
Sift4G
Benign
0.076
T
Polyphen
0.55
P
Vest4
0.65
MutPred
0.71
Loss of sheet (P = 0.0126);
MVP
0.90
MPC
0.043
ClinPred
0.17
T
GERP RS
5.6
Varity_R
0.33
gMVP
0.67

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs548536938; hg19: chr1-116247859; API