rs185237690

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001035.3(RYR2):ā€‹c.4652A>Gā€‹(p.Asn1551Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,613,046 control chromosomes in the GnomAD database, including 1 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: š‘“ 0.00019 ( 0 hom., cov: 33)
Exomes š‘“: 0.00014 ( 1 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

2
6
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 7.57
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.016109437).
BP6
Variant 1-237602080-A-G is Benign according to our data. Variant chr1-237602080-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201172.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=2}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00019 (29/152272) while in subpopulation EAS AF= 0.00464 (24/5176). AF 95% confidence interval is 0.0032. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RYR2NM_001035.3 linkuse as main transcriptc.4652A>G p.Asn1551Ser missense_variant 35/105 ENST00000366574.7 NP_001026.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RYR2ENST00000366574.7 linkuse as main transcriptc.4652A>G p.Asn1551Ser missense_variant 35/1051 NM_001035.3 ENSP00000355533 P1Q92736-1
RYR2ENST00000660292.2 linkuse as main transcriptc.4652A>G p.Asn1551Ser missense_variant 35/106 ENSP00000499787
RYR2ENST00000659194.3 linkuse as main transcriptc.4652A>G p.Asn1551Ser missense_variant 35/105 ENSP00000499653
RYR2ENST00000609119.2 linkuse as main transcriptc.4652A>G p.Asn1551Ser missense_variant, NMD_transcript_variant 35/1045 ENSP00000499659

Frequencies

GnomAD3 genomes
AF:
0.000191
AC:
29
AN:
152154
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00463
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000290
AC:
72
AN:
248478
Hom.:
0
AF XY:
0.000245
AC XY:
33
AN XY:
134814
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00379
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000355
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000141
AC:
206
AN:
1460774
Hom.:
1
Cov.:
30
AF XY:
0.000142
AC XY:
103
AN XY:
726640
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00450
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000225
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.000190
AC:
29
AN:
152272
Hom.:
0
Cov.:
33
AF XY:
0.000269
AC XY:
20
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00464
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000242
ExAC
AF:
0.000340
AC:
41
Asia WGS
AF:
0.00173
AC:
6
AN:
3476
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:9
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1Benign:3
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 03, 2024- -
Uncertain significance, criteria provided, single submitterreference populationSoonchunhyang University Bucheon Hospital, Soonchunhyang University Medical CenterMar 18, 2016- -
not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingGeneDxNov 20, 2018This variant is associated with the following publications: (PMID: 26498160, 23595086, 27452199, 26332594, 27756708, 27538377) -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Arrhythmogenic right ventricular dysplasia 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 15, 2023- -
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 29, 2018- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 11, 2016This 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
0.065
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.50
T;T
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Pathogenic
0.45
D
MetaRNN
Benign
0.016
T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
1.4
L;.
MutationTaster
Benign
0.98
D
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-2.2
N;.
REVEL
Benign
0.22
Sift
Benign
0.29
T;.
Polyphen
0.66
P;.
Vest4
0.38
MVP
0.57
MPC
0.98
ClinPred
0.18
T
GERP RS
5.5
Varity_R
0.16
gMVP
0.31

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: rs185237690; hg19: chr1-237765380; COSMIC: COSV63690141; API