rs550691734

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PP2PP3BP4BP6BS1BS2

The NM_001035.3(RYR2):​c.8798T>G​(p.Val2933Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000522 in 1,609,840 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).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

8
6
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 7.67

Publications

2 publications found
Variant links:
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]
RYR2 Gene-Disease associations (from GenCC):
  • arrhythmogenic right ventricular dysplasia 2
    Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
  • catecholaminergic polymorphic ventricular tachycardia
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
  • catecholaminergic polymorphic ventricular tachycardia 1
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • hypertrophic cardiomyopathy
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • arrhythmogenic right ventricular cardiomyopathy
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP2
Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, arrhythmogenic right ventricular cardiomyopathy.
PP3
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.4162286).
BP6
Variant 1-237674814-T-G is Benign according to our data. Variant chr1-237674814-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 404201.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000525 (8/152254) while in subpopulation SAS AF = 0.000622 (3/4822). AF 95% confidence interval is 0.000169. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR2NM_001035.3 linkc.8798T>G p.Val2933Gly missense_variant Exon 60 of 105 ENST00000366574.7 NP_001026.2 Q92736-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RYR2ENST00000366574.7 linkc.8798T>G p.Val2933Gly missense_variant Exon 60 of 105 1 NM_001035.3 ENSP00000355533.2 Q92736-1
RYR2ENST00000661330.2 linkc.8798T>G p.Val2933Gly missense_variant Exon 60 of 106 ENSP00000499393.2 A0A590UJF6
RYR2ENST00000609119.2 linkn.8798T>G non_coding_transcript_exon_variant Exon 60 of 104 5 ENSP00000499659.2 A0A590UK06

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000149
AC:
37
AN:
248540
AF XY:
0.000222
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000233
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000266
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000521
AC:
76
AN:
1457586
Hom.:
0
Cov.:
29
AF XY:
0.0000786
AC XY:
57
AN XY:
725246
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33392
American (AMR)
AF:
0.000202
AC:
9
AN:
44646
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26044
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39636
South Asian (SAS)
AF:
0.000593
AC:
51
AN:
85986
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53360
Middle Eastern (MID)
AF:
0.000347
AC:
2
AN:
5756
European-Non Finnish (NFE)
AF:
0.00000902
AC:
10
AN:
1108532
Other (OTH)
AF:
0.0000498
AC:
3
AN:
60234
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
4
8
11
15
19
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152254
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74464
show subpopulations
African (AFR)
AF:
0.0000481
AC:
2
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:
5182
South Asian (SAS)
AF:
0.000622
AC:
3
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67966
Other (OTH)
AF:
0.00
AC:
0
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.531
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000341
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.000174
AC:
21

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
Aug 06, 2024
All of Us Research Program, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces valine with glycine at codon 2933 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 38/279924 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
Jun 01, 2023
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces valine with glycine at codon 2933 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 38/279924 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. -

not provided Uncertain:1
Jul 17, 2024
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Reported in association with sudden cardiac arrest, however, detailed clinical information was not provided (PMID: 29884292); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); This variant is associated with the following publications: (PMID: 29884292, 19926015) -

not specified Benign:1
Jun 13, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: RYR2 c.8798T>G (p.Val2933Gly) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 0.00015 in 248540 control chromosomes. The observed variant frequency is approximately 4.33 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05). To our knowledge, no occurrence of c.8798T>G in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 404201). Based on the evidence outlined above, the variant was classified as likely benign. -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Jan 12, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Cardiovascular phenotype Benign:1
Jun 30, 2021
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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
Pathogenic
0.74
BayesDel_addAF
Uncertain
0.070
D
BayesDel_noAF
Pathogenic
0.25
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D;T
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.83
T;T
M_CAP
Pathogenic
0.87
D
MetaRNN
Benign
0.42
T;T
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
1.6
L;.
PhyloP100
7.7
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-5.1
D;.
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0010
D;.
Polyphen
0.99
D;.
Vest4
0.67
MutPred
0.60
Loss of stability (P = 0.0097);.;
MVP
0.82
MPC
1.2
ClinPred
0.20
T
GERP RS
4.9
Varity_R
0.71
gMVP
0.70
Mutation Taster
=15/85
disease causing

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

Other links and lift over

dbSNP: rs550691734; hg19: chr1-237838114; API