chr1-237614671-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_001035.3(RYR2):ā€‹c.5543C>Gā€‹(p.Pro1848Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

10
7
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91
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 Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RYR2NM_001035.3 linkuse as main transcriptc.5543C>G p.Pro1848Arg missense_variant 37/105 ENST00000366574.7 NP_001026.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RYR2ENST00000366574.7 linkuse as main transcriptc.5543C>G p.Pro1848Arg missense_variant 37/1051 NM_001035.3 ENSP00000355533 P1Q92736-1
RYR2ENST00000660292.2 linkuse as main transcriptc.5543C>G p.Pro1848Arg missense_variant 37/106 ENSP00000499787
RYR2ENST00000659194.3 linkuse as main transcriptc.5543C>G p.Pro1848Arg missense_variant 37/105 ENSP00000499653
RYR2ENST00000609119.2 linkuse as main transcriptc.5543C>G p.Pro1848Arg missense_variant, NMD_transcript_variant 37/1045 ENSP00000499659

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
248544
Hom.:
0
AF XY:
0.00000742
AC XY:
1
AN XY:
134830
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461708
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.69
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.20
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
D;D
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Uncertain
0.092
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Uncertain
0.11
D
MutationAssessor
Uncertain
2.7
M;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-6.3
D;.
REVEL
Pathogenic
0.78
Sift
Uncertain
0.0010
D;.
Polyphen
1.0
D;.
Vest4
0.96
MutPred
0.62
Loss of helix (P = 0.028);.;
MVP
0.76
MPC
1.2
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.78
gMVP
0.79

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: rs397516543; hg19: chr1-237777971; API