NM_001036.6:c.7613C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001036.6(RYR3):​c.7613C>T​(p.Thr2538Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,822 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 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

11
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

Publications

3 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.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR3NM_001036.6 linkc.7613C>T p.Thr2538Met missense_variant Exon 50 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.7613C>T p.Thr2538Met missense_variant Exon 50 of 104 1 NM_001036.6 ENSP00000489262.1 Q15413-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152150
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000803
AC:
20
AN:
249110
AF XY:
0.000111
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000556
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.0000354
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000424
AC:
62
AN:
1461672
Hom.:
0
Cov.:
31
AF XY:
0.0000564
AC XY:
41
AN XY:
727126
show subpopulations
African (AFR)
AF:
0.0000598
AC:
2
AN:
33472
American (AMR)
AF:
0.0000224
AC:
1
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39700
South Asian (SAS)
AF:
0.000348
AC:
30
AN:
86258
European-Finnish (FIN)
AF:
0.0000375
AC:
2
AN:
53402
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000207
AC:
23
AN:
1111840
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60374
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.452
Heterozygous variant carriers
0
4
8
12
16
20
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152150
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74322
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41430
American (AMR)
AF:
0.00
AC:
0
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.000192
AC:
1
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.000377
AC:
4
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000910
AC:
11

ClinVar

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

Submissions by phenotype

Epileptic encephalopathy Uncertain:1
Jun 04, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2538 of the RYR3 protein (p.Thr2538Met). This variant is present in population databases (rs576237958, gnomAD 0.04%). 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: 580185). 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 disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.49
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D;.;.;.;.
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.85
D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.7
M;M;.;.;.
PhyloP100
7.9
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-4.8
.;D;.;.;.
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
.;D;.;.;.
Polyphen
1.0
D;D;.;.;.
Vest4
0.79
MVP
0.97
MPC
0.72
ClinPred
0.86
D
GERP RS
5.7
Varity_R
0.69
gMVP
0.80
Mutation Taster
=32/68
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs576237958; hg19: chr15-34030748; COSMIC: COSV66777931; API