chr1-237595526-T-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_001035.3(RYR2):​c.4465T>A​(p.Cys1489Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1489R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RYR2
NM_001035.3 missense

Scores

1
11
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.01

Publications

6 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

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR2NM_001035.3 linkc.4465T>A p.Cys1489Ser missense_variant Exon 34 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.4465T>A p.Cys1489Ser missense_variant Exon 34 of 105 1 NM_001035.3 ENSP00000355533.2 Q92736-1
RYR2ENST00000661330.2 linkc.4465T>A p.Cys1489Ser missense_variant Exon 34 of 106 ENSP00000499393.2 A0A590UJF6
RYR2ENST00000609119.2 linkn.4465T>A non_coding_transcript_exon_variant Exon 34 of 104 5 ENSP00000499659.2 A0A590UK06

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Uncertain
0.053
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.56
D;T
Eigen
Benign
0.13
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Benign
0.028
D
MetaRNN
Uncertain
0.67
D;D
MetaSVM
Benign
-0.75
T
MutationAssessor
Uncertain
2.2
M;.
PhyloP100
8.0
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-4.1
D;.
REVEL
Uncertain
0.32
Sift
Benign
0.13
T;.
Polyphen
0.0070
B;.
Vest4
0.77
MutPred
0.69
Gain of disorder (P = 0.0017);.;
MVP
0.42
MPC
0.81
ClinPred
0.98
D
GERP RS
5.5
Varity_R
0.38
gMVP
0.64
Mutation Taster
=20/80
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.40
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.40
Position offset: -28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs200450676; hg19: chr1-237758826; API