rs199638420
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_001036.6(RYR3):āc.2770A>Gā(p.Thr924Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000462 in 1,589,930 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00060 ( 0 hom., cov: 33)
Exomes š: 0.00045 ( 0 hom. )
Consequence
RYR3
NM_001036.6 missense
NM_001036.6 missense
Scores
1
3
11
Clinical Significance
Conservation
PhyloP100: 5.80
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 Likely_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.015210718).
BP6
?
Variant 15-33630030-A-G is Benign according to our data. Variant chr15-33630030-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461897.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR3 | NM_001036.6 | c.2770A>G | p.Thr924Ala | missense_variant | 22/104 | ENST00000634891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR3 | ENST00000634891.2 | c.2770A>G | p.Thr924Ala | missense_variant | 22/104 | 1 | NM_001036.6 | P4 | |
RYR3 | ENST00000389232.9 | c.2770A>G | p.Thr924Ala | missense_variant | 22/104 | 5 | A1 | ||
RYR3 | ENST00000415757.7 | c.2770A>G | p.Thr924Ala | missense_variant | 22/103 | 2 | A2 | ||
RYR3 | ENST00000634418.1 | c.2770A>G | p.Thr924Ala | missense_variant | 22/102 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000598 AC: 91AN: 152214Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000635 AC: 142AN: 223724Hom.: 0 AF XY: 0.000675 AC XY: 81AN XY: 119978
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GnomAD4 exome AF: 0.000448 AC: 644AN: 1437598Hom.: 0 Cov.: 26 AF XY: 0.000468 AC XY: 334AN XY: 713994
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GnomAD4 genome ? AF: 0.000597 AC: 91AN: 152332Hom.: 0 Cov.: 33 AF XY: 0.000456 AC XY: 34AN XY: 74496
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 11, 2021 | The c.2770A>G (p.T924A) alteration is located in exon 22 (coding exon 22) of the RYR3 gene. This alteration results from a A to G substitution at nucleotide position 2770, causing the threonine (T) at amino acid position 924 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Epileptic encephalopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2022 | - - |
RYR3-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 12, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;.;.;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Polyphen
B;P;.;.;.
Vest4
MVP
0.83
MPC
0.25
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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