15-33660334-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001036.6(RYR3):c.4533G>C(p.Glu1511Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000195 in 1,439,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.484

Publications

0 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

RYR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18157268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.4533G>C	p.Glu1511Asp	missense_variant	Exon 34 of 104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RYR3	ENST00000634891.2 link	c.4533G>C	p.Glu1511Asp	missense_variant	Exon 34 of 104	1	NM_001036.6	ENSP00000489262.1
RYR3	ENST00000389232.9 link	c.4533G>C	p.Glu1511Asp	missense_variant	Exon 34 of 104	5		ENSP00000373884.5
RYR3	ENST00000415757.7 link	c.4533G>C	p.Glu1511Asp	missense_variant	Exon 34 of 103	2		ENSP00000399610.3
RYR3	ENST00000634418.1 link	c.4533G>C	p.Glu1511Asp	missense_variant	Exon 34 of 102	5		ENSP00000489529.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000470

AC:

AN:

212570

AF XY:

0.00000874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000195

AC:

AN:

1439424

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

713460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33054

American (AMR)

AF:

0.00

AC:

AN:

41542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25746

East Asian (EAS)

AF:

0.00

AC:

AN:

38486

South Asian (SAS)

AF:

0.00

AC:

AN:

82034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000200

AC:

AN:

1101462

Other (OTH)

AF:

0.000101

AC:

AN:

59600

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Uncertain:1

Mar 04, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is present in population databases (rs772574630, ExAC 0.005%). This variant has not been reported in the literature in individuals with RYR3-related conditions. ClinVar contains an entry for this variant (Variation ID: 566062). 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 C35"). 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 glutamic acid with aspartic acid at codon 1511 of the RYR3 protein (p.Glu1511Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.33

T;.;.;.;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.80

T;T;T;T;T

M_CAP

Benign

0.069

MetaRNN

Benign

0.18

T;T;T;T;T

MetaSVM

Uncertain

-0.011

MutationAssessor

Benign

0.69

N;N;.;.;.

PhyloP100

0.48

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.92

.;N;N;.;.

REVEL

Uncertain

0.31

Sift

Benign

0.51

.;T;T;.;.

Polyphen

0.0

B;B;.;.;.

Vest4

0.40

MutPred

0.30

Loss of methylation at K1509 (P = 0.0823);Loss of methylation at K1509 (P = 0.0823);Loss of methylation at K1509 (P = 0.0823);Loss of methylation at K1509 (P = 0.0823);Loss of methylation at K1509 (P = 0.0823);

MVP

0.43

MPC

0.16

ClinPred

0.042

GERP RS

1.9

Varity_R

0.085

gMVP

0.40

Mutation Taster

=72/28

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over