rs373358710
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001036.6(RYR3):c.6937G>A(p.Ala2313Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
RYR3
NM_001036.6 missense
NM_001036.6 missense
Scores
11
3
1
Clinical Significance
Conservation
PhyloP100: 8.03
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.897
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR3 | NM_001036.6 | c.6937G>A | p.Ala2313Thr | missense_variant | 46/104 | ENST00000634891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR3 | ENST00000634891.2 | c.6937G>A | p.Ala2313Thr | missense_variant | 46/104 | 1 | NM_001036.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152218Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460748Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726478
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74364
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR3 protein function. ClinVar contains an entry for this variant (Variation ID: 530980). This variant has not been reported in the literature in individuals affected with RYR3-related conditions. This variant is present in population databases (rs373358710, gnomAD 0.01%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2313 of the RYR3 protein (p.Ala2313Thr). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Pathogenic
DEOGEN2
Uncertain
D;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Polyphen
D;D;.;.;.
Vest4
MVP
0.88
MPC
0.70
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at