1-237566750-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PP2BP4BS1

The NM_001035.3(RYR2):​c.3398G>C​(p.Arg1133Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. R1133C) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

1
5
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.59
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 Likely_benign. Variant got -2 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, 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=0.30648547).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000197 (3/152204) while in subpopulation AMR AF= 0.000196 (3/15284). AF 95% confidence interval is 0.0000528. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR2NM_001035.3 linkc.3398G>C p.Arg1133Pro missense_variant Exon 28 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.3398G>C p.Arg1133Pro missense_variant Exon 28 of 105 1 NM_001035.3 ENSP00000355533.2 Q92736-1
RYR2ENST00000609119.2 linkn.3398G>C non_coding_transcript_exon_variant Exon 28 of 104 5 ENSP00000499659.2 A0A590UK06
RYR2ENST00000660292.2 linkc.3398G>C p.Arg1133Pro missense_variant Exon 28 of 106 ENSP00000499787.2 A0A590UKB7
RYR2ENST00000659194.3 linkc.3398G>C p.Arg1133Pro missense_variant Exon 28 of 105 ENSP00000499653.3 A0A590UJZ8

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.00000401
AC:
1
AN:
249172
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135182
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
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:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461662
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727114
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152204
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
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
Bravo
AF:
0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Benign
-0.059
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.52
D;T
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.47
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.31
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
L;.
PrimateAI
Benign
0.26
T
PROVEAN
Uncertain
-2.6
D;D
REVEL
Benign
0.22
Sift
Benign
0.29
T;D
Polyphen
0.033
B;.
Vest4
0.63
MutPred
0.67
Gain of glycosylation at S1130 (P = 0.0539);.;
MVP
0.84
MPC
0.60
ClinPred
0.13
T
GERP RS
-0.96
Varity_R
0.40
gMVP
0.87

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: rs374397612; hg19: chr1-237730050; API