chr1-237454494-C-G
Position:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2
The ENST00000366574.7(RYR2):āc.1396C>Gā(p.Pro466Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P466Q) has been classified as Uncertain significance.
Frequency
Genomes: š 0.000059 ( 0 hom., cov: 32)
Exomes š: 0.000043 ( 0 hom. )
Consequence
RYR2
ENST00000366574.7 missense
ENST00000366574.7 missense
Scores
9
6
3
Clinical Significance
Conservation
PhyloP100: 7.90
Genes affected
RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR2. . Gene score misZ 5.7809 (greater than the threshold 3.09). Trascript score misZ 6.4158 (greater than threshold 3.09). GenCC has associacion of gene with hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.88
BS2
High AC in GnomAd4 at 9 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RYR2 | NM_001035.3 | c.1396C>G | p.Pro466Ala | missense_variant | 15/105 | ENST00000366574.7 | NP_001026.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR2 | ENST00000366574.7 | c.1396C>G | p.Pro466Ala | missense_variant | 15/105 | 1 | NM_001035.3 | ENSP00000355533 | P1 | |
| RYR2 | ENST00000660292.2 | c.1396C>G | p.Pro466Ala | missense_variant | 15/106 | ENSP00000499787 | ||||
| RYR2 | ENST00000659194.3 | c.1396C>G | p.Pro466Ala | missense_variant | 15/105 | ENSP00000499653 | ||||
| RYR2 | ENST00000609119.2 | c.1396C>G | p.Pro466Ala | missense_variant, NMD_transcript_variant | 15/104 | 5 | ENSP00000499659 |
Frequencies
GnomAD3 genomes 0.0000592 AC: 9AN: 152074Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
9
AN:
152074
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000105 AC: 26AN: 248716Hom.: 0 AF XY: 0.0000815 AC XY: 11AN XY: 134904
GnomAD3 exomes
AF:
AC:
26
AN:
248716
Hom.:
AF XY:
AC XY:
11
AN XY:
134904
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461334Hom.: 0 Cov.: 33 AF XY: 0.0000481 AC XY: 35AN XY: 726938
GnomAD4 exome
AF:
AC:
63
AN:
1461334
Hom.:
Cov.:
33
AF XY:
AC XY:
35
AN XY:
726938
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.0000592 AC: 9AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74278
GnomAD4 genome
AF:
AC:
9
AN:
152074
Hom.:
Cov.:
32
AF XY:
AC XY:
3
AN XY:
74278
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
2
ExAC
AF:
AC:
14
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
| Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 31, 2020 | Reported in an individual with aborted cardiac arrest and a family history of multiple people with sudden cardiac death (Tester et al., 2005); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 161383; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009); This variant is associated with the following publications: (PMID: 32048431, 25637381, 23861362, 19926015, 24025405, 28404607, 16188589, 27538377, 29555771, 31980526, 33825858) - |
| Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Polymorphic ventricular tachycardia Uncertain:2
| Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Apr 05, 2018 | - - |
| Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 10, 2024 | This missense variant replaces proline with alanine at codon 466 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experiment has shown that this variant has no impact on caffeine-induced calcium release in cultured cells (PMID: 33825858). However, the clinical relevance of this observation is not known. This variant has been reported in a young individual with aborted cardiac arrest and a family history of sudden cardiac death (PMID: 16188589), in an individual with a cardiomyopathy diagnosis (PMID: 32009526), and in an infant with recurrent apparent life-threatening event followed by sudden cardiac death (Hernandez et al., 2016). This variant has also been identified in 28/280104 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 22, 2023 | This missense variant replaces proline with alanine at codon 466 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experiment has shown that this variant has no impact on caffeine-induced calcium release in cultured cells (PMID: 33825858). However, the clinical relevance of this observation is not known. This variant has been reported in a young individual with aborted cardiac arrest and a family history of sudden cardiac death (PMID: 16188589), in an individual with a cardiomyopathy diagnosis (PMID: 32009526), and in an infant with recurrent apparent life-threatening event followed by sudden cardiac death (Hernandez et al., 2016). This variant has also been identified in 28/280104 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 29, 2023 | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 466 of the RYR2 protein (p.Pro466Ala). This variant is present in population databases (rs376612295, gnomAD 0.03%). This missense change has been observed in individual(s) with aborted cardiac arrest or catecholaminergic polymorphic ventricular tachycardia (PMID: 16188589, 28404607, 29555771, 32009526, 32152366). ClinVar contains an entry for this variant (Variation ID: 161383). 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 expected to disrupt RYR2 protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RYR2 function (PMID: 33825858). 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. - |
Arrhythmogenic right ventricular dysplasia 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 08, 2023 | The p.P466A variant (also known as c.1396C>G), located in coding exon 15 of the RYR2 gene, results from a C to G substitution at nucleotide position 1396. The proline at codon 466 is replaced by alanine, an amino acid with highly similar properties. This variant has been reported in a number of individuals with a variety of cardiac disease phenotypes, including cardiac arrest, left ventricular hypertrophy, and ventricular tachycardia (Tester DJ et al. Heart Rhythm, 2005 Oct;2:1099-105; Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Pottinger TD et al. J Am Heart Assoc, 2020 02;9:e013808). However, this variant has also been reported in exome cohorts (Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Pathogenic
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at