rs561321743

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000366574.7(RYR2):ā€‹c.2630A>Cā€‹(p.His877Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,612,868 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 Likely benign (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H877Y) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.00011 ( 0 hom., cov: 33)
Exomes š‘“: 0.00015 ( 0 hom. )

Consequence

RYR2
ENST00000366574.7 missense

Scores

10
4
4

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: 9.32
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 -19 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=0.022494674).
BP6
Variant 1-237506726-A-C is Benign according to our data. Variant chr1-237506726-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 180489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000105 (16/152270) while in subpopulation AMR AF= 0.00105 (16/15306). AF 95% confidence interval is 0.000655. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RYR2NM_001035.3 linkuse as main transcriptc.2630A>C p.His877Pro missense_variant 23/105 ENST00000366574.7 NP_001026.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RYR2ENST00000366574.7 linkuse as main transcriptc.2630A>C p.His877Pro missense_variant 23/1051 NM_001035.3 ENSP00000355533 P1Q92736-1
RYR2ENST00000660292.2 linkuse as main transcriptc.2630A>C p.His877Pro missense_variant 23/106 ENSP00000499787
RYR2ENST00000659194.3 linkuse as main transcriptc.2630A>C p.His877Pro missense_variant 23/105 ENSP00000499653
RYR2ENST00000609119.2 linkuse as main transcriptc.2630A>C p.His877Pro missense_variant, NMD_transcript_variant 23/1045 ENSP00000499659

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152152
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000799
AC:
198
AN:
247924
Hom.:
0
AF XY:
0.000573
AC XY:
77
AN XY:
134438
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00565
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000664
GnomAD4 exome
AF:
0.000153
AC:
223
AN:
1460598
Hom.:
0
Cov.:
30
AF XY:
0.000125
AC XY:
91
AN XY:
726448
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00493
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:
0.00
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152270
Hom.:
0
Cov.:
33
AF XY:
0.000107
AC XY:
8
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00105
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000482
Hom.:
0
Bravo
AF:
0.000555
ExAC
AF:
0.000745
AC:
90

ClinVar

Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 05, 2018Variant summary: RYR2 c.2630A>C (p.His877Pro) results in a non-conservative amino acid change located in the Ryanodine receptor Ryr domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00071 in 276002 control chromosomes, predominantly within the Latino subpopulation at a frequency of 0.0055 in the gnomAD database. The observed variant frequency within Latino control individuals is approximately 92-fold above the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.2630A>C in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 20, 2015- -
not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 01, 2019- -
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 13, 2020This variant is associated with the following publications: (PMID: 28404607) -
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingBlueprint GeneticsOct 07, 2014- -
Cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthOct 03, 2018- -
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 30, 2023- -
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingCenter for Advanced Laboratory Medicine, UC San Diego Health, University of California San DiegoDec 24, 2018- -
RYR2-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 08, 2024This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 11, 2018This 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
0.31
BayesDel_addAF
Benign
-0.026
T
BayesDel_noAF
Pathogenic
0.19
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.90
D;T
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.97
D;D
M_CAP
Pathogenic
0.51
D
MetaRNN
Benign
0.022
T;T
MetaSVM
Pathogenic
0.84
D
MutationAssessor
Uncertain
2.1
M;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-6.5
D;.
REVEL
Pathogenic
0.86
Sift
Uncertain
0.010
D;.
Polyphen
1.0
D;.
Vest4
0.79
MutPred
0.63
Gain of glycosylation at H877 (P = 0.0464);.;
MVP
0.79
MPC
1.4
ClinPred
0.13
T
GERP RS
5.6
Varity_R
0.84
gMVP
0.85

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: rs561321743; hg19: chr1-237670026; API