chr15-33722851-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001036.6(RYR3):​c.6756G>C​(p.Glu2252Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,952 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

1
12
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52

Publications

0 publications found
Variant links:
Genes affected
RYR3 (HGNC:10485): (ryanodine receptor 3) The protein encoded by this gene is a ryanodine receptor, which functions to release calcium from intracellular storage for use in many cellular processes. For example, the encoded protein is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum followed by depolarization of T-tubules. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]
RYR3 Gene-Disease associations (from GenCC):
  • genetic developmental and epileptic encephalopathy
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen, G2P
  • congenital myopathy
    Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR3NM_001036.6 linkc.6756G>C p.Glu2252Asp missense_variant Exon 44 of 104 ENST00000634891.2 NP_001027.3 Q15413-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RYR3ENST00000634891.2 linkc.6756G>C p.Glu2252Asp missense_variant Exon 44 of 104 1 NM_001036.6 ENSP00000489262.1 Q15413-1
RYR3ENST00000389232.9 linkc.6756G>C p.Glu2252Asp missense_variant Exon 44 of 104 5 ENSP00000373884.5 A0A0X1KG73
RYR3ENST00000415757.7 linkc.6756G>C p.Glu2252Asp missense_variant Exon 44 of 103 2 ENSP00000399610.3 Q15413-2
RYR3ENST00000634418.1 linkc.6756G>C p.Glu2252Asp missense_variant Exon 44 of 102 5 ENSP00000489529.1 A0A0U1RRH1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00000415
AC:
1
AN:
241208
AF XY:
0.00000761
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000900
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.89e-7
AC:
1
AN:
1451952
Hom.:
0
Cov.:
32
AF XY:
0.00000139
AC XY:
1
AN XY:
721932
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32746
American (AMR)
AF:
0.00
AC:
0
AN:
41734
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25718
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39536
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85300
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53322
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5736
European-Non Finnish (NFE)
AF:
9.03e-7
AC:
1
AN:
1107894
Other (OTH)
AF:
0.00
AC:
0
AN:
59966
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000827
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Epileptic encephalopathy Uncertain:1
Jun 14, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with RYR3-related disease. This variant is present in population databases (rs760270042, ExAC 0.002%). This sequence change replaces glutamic acid with aspartic acid at codon 2252 of the RYR3 protein (p.Glu2252Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.46
T;.;.;.;.
Eigen
Benign
0.084
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.94
D;D;D;D;D
M_CAP
Uncertain
0.095
D
MetaRNN
Uncertain
0.69
D;D;D;D;D
MetaSVM
Uncertain
0.78
D
MutationAssessor
Uncertain
2.4
M;M;.;.;.
PhyloP100
2.5
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-2.4
.;N;N;.;.
REVEL
Uncertain
0.50
Sift
Benign
0.082
.;T;T;.;.
Polyphen
0.47
P;B;.;.;.
Vest4
0.72
MutPred
0.29
Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);
MVP
0.86
MPC
0.19
ClinPred
0.66
D
GERP RS
4.9
Varity_R
0.30
gMVP
0.70
Mutation Taster
=57/43
polymorphism

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

Other links and lift over

dbSNP: rs760270042; hg19: chr15-34015052; API