rs59021219

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001036.6(RYR3):c.5033A>G(p.Asp1678Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00632 in 1,613,842 control chromosomes in the GnomAD database, including 534 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1678E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.034 ( 281 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 253 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.95

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

RYR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017106831).

BP6

Variant 15-33662563-A-G is Benign according to our data. Variant chr15-33662563-A-G is described in ClinVar as Benign. ClinVar VariationId is 461920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001036.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.5033A>G	p.Asp1678Gly	missense	Exon 35 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.5033A>G	p.Asp1678Gly	missense	Exon 35 of 103	NP_001230925.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RYR3	ENST00000634891.2	TSL:1 MANE Select	c.5033A>G	p.Asp1678Gly	missense	Exon 35 of 104	ENSP00000489262.1
RYR3	ENST00000389232.9	TSL:5	c.5033A>G	p.Asp1678Gly	missense	Exon 35 of 104	ENSP00000373884.5
RYR3	ENST00000415757.7	TSL:2	c.5033A>G	p.Asp1678Gly	missense	Exon 35 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes

AF:

0.0336

AC:

5108

AN:

152016

Hom.:

282

Cov.:

show subpopulations

Gnomad AFR

AF:

0.116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000721

Gnomad OTH

AF:

0.0210

GnomAD2 exomes

AF:

0.00896

AC:

2233

AN:

249294

AF XY:

0.00665

show subpopulations

Gnomad AFR exome

AF:

0.122

Gnomad AMR exome

AF:

0.00637

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000522

Gnomad OTH exome

AF:

0.00512

GnomAD4 exome

AF:

0.00348

AC:

5082

AN:

1461708

Hom.:

253

Cov.:

AF XY:

0.00295

AC XY:

2142

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.113

AC:

3788

AN:

33480

American (AMR)

AF:

0.00742

AC:

332

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00417

AC:

109

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000220

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000330

AC:

367

AN:

1111868

Other (OTH)

AF:

0.00745

AC:

450

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

330

661

991

1322

1652

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.0336

AC:

5114

AN:

152134

Hom.:

281

Cov.:

AF XY:

0.0320

AC XY:

2376

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.116

AC:

4821

AN:

41486

American (AMR)

AF:

0.0116

AC:

177

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000721

AC:

AN:

67994

Other (OTH)

AF:

0.0208

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

241

482

723

964

1205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0122

Hom.:

207

Bravo

AF:

0.0389

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.114

AC:

453

ESP6500EA

AF:

0.000602

AC:

ExAC

AF:

0.0106

AC:

1283

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.38

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

4.9

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.0

REVEL

Benign

0.20

Sift

Benign

0.37

Polyphen

0.081

Vest4

0.17

MPC

0.25

ClinPred

0.017

GERP RS

5.2

Varity_R

0.19

gMVP

0.45

Mutation Taster

=99/1

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over