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rs202015519

Variant summary

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

The NM_001035.3(RYR2):c.2935G>T(p.Ala979Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000141 in 1,613,942 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A979V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00057 ( 1 hom., cov: 33)
Exomes 𝑓: 0.000096 ( 3 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

1
10
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 4.74
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2
Missense variant where missense usually causes diseases, RYR2
BP4
Computational evidence support a benign effect (MetaRNN=0.05739823).
BP6
Variant 1-237548459-G-T is Benign according to our data. Variant chr1-237548459-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178118.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=1, Uncertain_significance=1}. Variant chr1-237548459-G-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000571 (87/152294) while in subpopulation AFR AF= 0.00204 (85/41574). AF 95% confidence interval is 0.00169. There are 1 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
High AC in GnomAd at 80 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RYR2NM_001035.3 linkuse as main transcriptc.2935G>T p.Ala979Ser missense_variant 26/105 ENST00000366574.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RYR2ENST00000366574.7 linkuse as main transcriptc.2935G>T p.Ala979Ser missense_variant 26/1051 NM_001035.3 P1Q92736-1
RYR2ENST00000660292.2 linkuse as main transcriptc.2935G>T p.Ala979Ser missense_variant 26/106
RYR2ENST00000659194.3 linkuse as main transcriptc.2935G>T p.Ala979Ser missense_variant 26/105
RYR2ENST00000609119.2 linkuse as main transcriptc.2935G>T p.Ala979Ser missense_variant, NMD_transcript_variant 26/1045

Frequencies

GnomAD3 genomes
AF:
0.000526
AC:
80
AN:
152176
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00188
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000141
AC:
35
AN:
249060
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135116
show subpopulations
Gnomad AFR exome
AF:
0.00181
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000331
GnomAD4 exome
AF:
0.0000965
AC:
141
AN:
1461648
Hom.:
3
Cov.:
30
AF XY:
0.0000866
AC XY:
63
AN XY:
727094
show subpopulations
Gnomad4 AFR exome
AF:
0.00290
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.000596
GnomAD4 genome
AF:
0.000571
AC:
87
AN:
152294
Hom.:
1
Cov.:
33
AF XY:
0.000658
AC XY:
49
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.00204
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000431
Hom.:
0
Bravo
AF:
0.000684
ESP6500AA
AF:
0.00237
AC:
9
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000157
AC:
19
Asia WGS
AF:
0.00260
AC:
9
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 01, 2020proposed classification - variant undergoing re-assessment, contact laboratory -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 29, 2021Variant summary: RYR2 c.2935G>T (p.Ala979Ser) results in a conservative amino acid change located in the Ryanodine receptor Ryr domain (IPR003032) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 249060 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 30 fold of 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 African or African-American origin. c.2935G>T has been reported in the literature in patients (Lopes_2015, Torkamani_2016, Landstrom_2017), however these data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, where five has classified the variant as benign/likely benign and two have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 24, 2024- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Arrhythmogenic right ventricular dysplasia 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 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. -
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthDec 17, 2018- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxOct 18, 2023See Variant Classification Assertion Criteria. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 29, 2020This alteration is classified as likely benign based on a combination of the following: 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
0.090
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.12
Cadd
Benign
23
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D;T
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.057
T;T
MetaSVM
Uncertain
0.58
D
MutationAssessor
Benign
1.5
L;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-2.5
D;.
REVEL
Uncertain
0.56
Sift
Benign
0.032
D;.
Polyphen
0.81
P;.
Vest4
0.30
MVP
0.75
MPC
0.76
ClinPred
0.031
T
GERP RS
5.8
Varity_R
0.27
gMVP
0.50

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: rs202015519; hg19: chr1-237711759; API