rs199648816

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3BP4BP6BS2

The NM_001036.6(RYR3):c.6698G>A(p.Arg2233Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,613,240 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R2233R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 5 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 10.0

Publications

5 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:

Y_RNA (HGNC:):

Y_RNA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Dann, M_CAP, phyloP100way_vertebrate, PrimateAI, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.2657218).

BP6

Variant 15-33722793-G-A is Benign according to our data. Variant chr15-33722793-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 461938.

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.6698G>A	p.Arg2233Gln	missense_variant	Exon 44 of 104	ENST00000634891.2	NP_001027.3	Q15413-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2 link	c.6698G>A	p.Arg2233Gln	missense_variant	Exon 44 of 104	1	NM_001036.6	ENSP00000489262.1		Q15413-1

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

156

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00165

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000725

AC:

180

AN:

248212

AF XY:

0.000824

show subpopulations

Gnomad AFR exome

AF:

0.000518

Gnomad AMR exome

AF:

0.000587

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000559

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00124

Gnomad OTH exome

AF:

0.000832

GnomAD4 exome

AF:

0.00169

AC:

2465

AN:

1460936

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

1182

AN XY:

726708

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33456

American (AMR)

AF:

0.000560

AC:

AN:

44612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39664

South Asian (SAS)

AF:

0.0000349

AC:

AN:

86000

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00205

AC:

2274

AN:

1111588

Other (OTH)

AF:

0.00229

AC:

138

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

115

230

344

459

574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<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:

0.00102

AC:

156

AN:

152304

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000601

AC:

AN:

41574

American (AMR)

AF:

0.000850

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00165

AC:

112

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.000994

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000507

AC:

ESP6500EA

AF:

0.00168

AC:

ExAC

AF:

0.000835

AC:

101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital myopathy 20

Uncertain:1

Jan 13, 2024

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3(Moderate),PM2 -

not provided

Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR3 NM_001036.4 exon 44 p.Arg2233Gln (c.6698G>A): This variant has not been reported in the literature but is present in 0.1% (102/64580) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-33722793-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:461938). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. Of note, splice prediction tools suggest that this variant may affect splicing through creation of a novel splice site. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Epileptic encephalopathy

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;.;.;.;.

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.27

T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

M;M;.;.;.

PhyloP100

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.6

.;D;D;.;.

REVEL

Pathogenic

0.81

Sift

Benign

0.031

.;D;D;.;.

Polyphen

0.97

D;D;.;.;.

Vest4

0.79

MVP

0.82

MPC

0.57

ClinPred

0.075

GERP RS

4.9

Varity_R

0.47

gMVP

0.81

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over