rs370044621

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001036.6(RYR3):ā€‹c.3952C>Gā€‹(p.Gln1318Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,455,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

1
6
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.09
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29191864).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RYR3NM_001036.6 linkuse as main transcriptc.3952C>G p.Gln1318Glu missense_variant 30/104 ENST00000634891.2 NP_001027.3 Q15413-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RYR3ENST00000634891.2 linkuse as main transcriptc.3952C>G p.Gln1318Glu missense_variant 30/1041 NM_001036.6 ENSP00000489262.1 Q15413-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1455280
Hom.:
0
Cov.:
27
AF XY:
0.00000138
AC XY:
1
AN XY:
724396
show subpopulations
Gnomad4 AFR exome
AF:
0.0000900
Gnomad4 AMR exome
AF:
0.00
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
Cov.:
32
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000122
AC:
1
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 27, 2022This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 1318 of the RYR3 protein (p.Gln1318Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RYR3-related conditions. ClinVar contains an entry for this variant (Variation ID: 461909). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
21
DANN
Benign
0.59
DEOGEN2
Benign
0.25
T;.;.;.;.
Eigen
Benign
-0.12
Eigen_PC
Benign
0.15
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D;D;D;D;D
M_CAP
Benign
0.060
D
MetaRNN
Benign
0.29
T;T;T;T;T
MetaSVM
Uncertain
0.018
D
MutationAssessor
Benign
-0.66
N;N;.;.;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
0.25
.;N;N;.;.
REVEL
Uncertain
0.43
Sift
Benign
0.60
.;T;T;.;.
Polyphen
0.12
B;B;.;.;.
Vest4
0.52
MVP
0.72
MPC
0.20
ClinPred
0.62
D
GERP RS
6.0
Varity_R
0.12
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs370044621; hg19: chr15-33939635; API