rs2229116

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.2191A>G(p.Ile731Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,612,830 control chromosomes in the GnomAD database, including 40,692 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3393 hom., cov: 32)

Exomes 𝑓: 0.22 ( 37299 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.446

Publications

53 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=0.0047627687).

BP6

Variant 15-33613209-A-G is Benign according to our data. Variant chr15-33613209-A-G is described in ClinVar as Benign. ClinVar VariationId is 1166904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.2191A>G	p.Ile731Val	missense_variant	Exon 19 of 104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RYR3	ENST00000634891.2 link	c.2191A>G	p.Ile731Val	missense_variant	Exon 19 of 104	1	NM_001036.6	ENSP00000489262.1
RYR3	ENST00000389232.9 link	c.2191A>G	p.Ile731Val	missense_variant	Exon 19 of 104	5		ENSP00000373884.5
RYR3	ENST00000415757.7 link	c.2191A>G	p.Ile731Val	missense_variant	Exon 19 of 103	2		ENSP00000399610.3
RYR3	ENST00000634418.1 link	c.2191A>G	p.Ile731Val	missense_variant	Exon 19 of 102	5		ENSP00000489529.1

Frequencies

GnomAD3 genomes

AF:

0.206

AC:

31366

AN:

151930

Hom.:

3386

Cov.:

show subpopulations

Gnomad AFR

AF:

0.152

Gnomad AMI

AF:

0.218

Gnomad AMR

AF:

0.268

Gnomad ASJ

AF:

0.157

Gnomad EAS

AF:

0.160

Gnomad SAS

AF:

0.240

Gnomad FIN

AF:

0.278

Gnomad MID

AF:

0.182

Gnomad NFE

AF:

0.219

Gnomad OTH

AF:

0.191

GnomAD2 exomes

AF:

0.230

AC:

56968

AN:

247702

AF XY:

0.228

show subpopulations

Gnomad AFR exome

AF:

0.148

Gnomad AMR exome

AF:

0.320

Gnomad ASJ exome

AF:

0.156

Gnomad EAS exome

AF:

0.156

Gnomad FIN exome

AF:

0.282

Gnomad NFE exome

AF:

0.218

Gnomad OTH exome

AF:

0.228

GnomAD4 exome

AF:

0.223

AC:

325218

AN:

1460780

Hom.:

37299

Cov.:

AF XY:

0.223

AC XY:

161949

AN XY:

726660

show subpopulations

African (AFR)

AF:

0.148

AC:

4948

AN:

33470

American (AMR)

AF:

0.316

AC:

14077

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.156

AC:

4085

AN:

26128

East Asian (EAS)

AF:

0.179

AC:

7116

AN:

39664

South Asian (SAS)

AF:

0.245

AC:

21125

AN:

86176

European-Finnish (FIN)

AF:

0.284

AC:

15132

AN:

53370

Middle Eastern (MID)

AF:

0.195

AC:

1126

AN:

5766

European-Non Finnish (NFE)

AF:

0.220

AC:

244758

AN:

1111248

Other (OTH)

AF:

0.213

AC:

12851

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

12067

24134

36200

48267

60334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8530

17060

25590

34120

42650

<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:

0.207

AC:

31408

AN:

152050

Hom.:

3393

Cov.:

AF XY:

0.211

AC XY:

15690

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.152

AC:

6316

AN:

41468

American (AMR)

AF:

0.269

AC:

4112

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

543

AN:

3462

East Asian (EAS)

AF:

0.159

AC:

823

AN:

5168

South Asian (SAS)

AF:

0.241

AC:

1160

AN:

4816

European-Finnish (FIN)

AF:

0.278

AC:

2936

AN:

10572

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.219

AC:

14864

AN:

67972

Other (OTH)

AF:

0.193

AC:

406

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1293

2585

3878

5170

6463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

344

688

1032

1376

1720

<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:

0.211

Hom.:

17336

Bravo

AF:

0.203

TwinsUK

AF:

0.226

AC:

837

ESP6500AA

AF:

0.138

AC:

576

ESP6500EA

AF:

0.215

AC:

1824

ExAC

AF:

0.226

AC:

27333

Asia WGS

AF:

0.215

AC:

747

AN:

3478

EpiCase

AF:

0.208

EpiControl

AF:

0.208

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Benign:1

Jan 22, 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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.23

T;.;.;.;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.23

LIST_S2

Benign

0.76

T;T;T;T;T

MetaRNN

Benign

0.0048

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

N;N;.;.;.

PhyloP100

0.45

PrimateAI

Benign

0.41

PROVEAN

Benign

0.0

.;N;N;.;.

Sift

Pathogenic

0.0

.;T;T;.;.

Sift4G

Pathogenic

0.0

.;.;.;.;.

Vest4

0.041

ClinPred

0.0042

GERP RS

3.1

Varity_R

0.023

gMVP

0.21

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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