rs116774472

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001035.3(RYR2):​c.5613C>T​(p.Asp1871Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000512 in 1,613,774 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

RYR2
NM_001035.3 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -1.02
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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
Variant 1-237614741-C-T is Benign according to our data. Variant chr1-237614741-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 138946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237614741-C-T is described in Lovd as [Benign]. Variant chr1-237614741-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-1.02 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00248 (378/152234) while in subpopulation AFR AF= 0.00831 (345/41538). AF 95% confidence interval is 0.00758. There are 0 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 378 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RYR2NM_001035.3 linkuse as main transcriptc.5613C>T p.Asp1871Asp synonymous_variant 37/105 ENST00000366574.7 NP_001026.2 Q92736-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RYR2ENST00000366574.7 linkuse as main transcriptc.5613C>T p.Asp1871Asp synonymous_variant 37/1051 NM_001035.3 ENSP00000355533.2 Q92736-1
RYR2ENST00000609119.2 linkuse as main transcriptn.5613C>T non_coding_transcript_exon_variant 37/1045 ENSP00000499659.2 A0A590UK06
RYR2ENST00000660292.2 linkuse as main transcriptc.5613C>T p.Asp1871Asp synonymous_variant 37/106 ENSP00000499787.2 A0A590UKB7
RYR2ENST00000659194.3 linkuse as main transcriptc.5613C>T p.Asp1871Asp synonymous_variant 37/105 ENSP00000499653.3 A0A590UJZ8

Frequencies

GnomAD3 genomes
AF:
0.00248
AC:
378
AN:
152116
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00833
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00124
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000649
AC:
161
AN:
247970
Hom.:
0
AF XY:
0.000580
AC XY:
78
AN XY:
134578
show subpopulations
Gnomad AFR exome
AF:
0.00844
Gnomad AMR exome
AF:
0.000319
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000558
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000134
Gnomad OTH exome
AF:
0.000499
GnomAD4 exome
AF:
0.000307
AC:
448
AN:
1461540
Hom.:
1
Cov.:
31
AF XY:
0.000287
AC XY:
209
AN XY:
727026
show subpopulations
Gnomad4 AFR exome
AF:
0.00938
Gnomad4 AMR exome
AF:
0.000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000639
Gnomad4 OTH exome
AF:
0.000629
GnomAD4 genome
AF:
0.00248
AC:
378
AN:
152234
Hom.:
0
Cov.:
32
AF XY:
0.00239
AC XY:
178
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.00831
Gnomad4 AMR
AF:
0.00124
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.00122
Hom.:
1
Bravo
AF:
0.00288
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2024RYR2: BP4, BP7, BS1 -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 28, 2023- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not specified Benign:4
Benign, criteria provided, single submitterclinical testingGeneDxJul 12, 2013This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 17, 2014Asp1871Asp in exon 37 of RYR2: This variant is not expected to have clinical sig nificance because it has been identified in 0.8% (31/4108) of African American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/; dbSNP rs116774472). -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 06, 2015- -
Cardiomyopathy Benign:2
Benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioOct 11, 2016- -
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 08, 2018- -
Catecholaminergic polymorphic ventricular tachycardia Benign:1
Benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthFeb 05, 2024- -
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 29, 2016This alteration is classified as 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
BayesDel_noAF
Benign
-0.84
CADD
Benign
0.14
DANN
Benign
0.30

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: rs116774472; hg19: chr1-237778041; COSMIC: COSV63675604; API