15-33644399-G-C

Variant summary

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

The NM_001036.6(RYR3):​c.3645G>C​(p.Met1215Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RYR3
NM_001036.6 missense

Scores

1
9
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.74
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]

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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=0.33244193).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR3NM_001036.6 linkc.3645G>C p.Met1215Ile missense_variant Exon 28 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.3645G>C p.Met1215Ile missense_variant Exon 28 of 104 1 NM_001036.6 ENSP00000489262.1 Q15413-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Epileptic encephalopathy Uncertain:1
Jul 12, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1215 of the RYR3 protein (p.Met1215Ile). 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: 461908). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.77
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
22
DANN
Benign
0.84
DEOGEN2
Benign
0.26
T;.;.;.;.
Eigen
Uncertain
0.22
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.92
D;D;D;D;D
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.33
T;T;T;T;T
MetaSVM
Uncertain
0.32
D
MutationAssessor
Benign
-0.41
N;N;.;.;.
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-0.10
.;N;N;.;.
REVEL
Uncertain
0.50
Sift
Benign
0.93
.;T;T;.;.
Polyphen
0.92
P;P;.;.;.
Vest4
0.44
MutPred
0.44
Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP
0.35
MPC
0.20
ClinPred
0.84
D
GERP RS
5.1
Varity_R
0.29
gMVP
0.75

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: rs908431118; hg19: chr15-33936600; API