15-33801900-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001036.6(RYR3):c.9950T>C(p.Ile3317Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,579,436 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 16 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 8.02

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010166019).

BP6

Variant 15-33801900-T-C is Benign according to our data. Variant chr15-33801900-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 461994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 16 AD,AR gene

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.9950T>C	p.Ile3317Thr	missense	Exon 69 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.9950T>C	p.Ile3317Thr	missense	Exon 69 of 103	NP_001230925.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RYR3	ENST00000634891.2	TSL:1 MANE Select	c.9950T>C	p.Ile3317Thr	missense	Exon 69 of 104	ENSP00000489262.1
RYR3	ENST00000389232.9	TSL:5	c.9947T>C	p.Ile3316Thr	missense	Exon 69 of 104	ENSP00000373884.5
RYR3	ENST00000415757.7	TSL:2	c.9950T>C	p.Ile3317Thr	missense	Exon 69 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes

AF:

0.00169

AC:

258

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00807

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00238

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00240

AC:

491

AN:

204946

AF XY:

0.00286

show subpopulations

Gnomad AFR exome

AF:

0.000486

Gnomad AMR exome

AF:

0.000555

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00240

Gnomad NFE exome

AF:

0.00220

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00277

AC:

3956

AN:

1427082

Hom.:

Cov.:

AF XY:

0.00296

AC XY:

2092

AN XY:

706976

show subpopulations

African (AFR)

AF:

0.000335

AC:

AN:

32862

American (AMR)

AF:

0.000581

AC:

AN:

39612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25498

East Asian (EAS)

AF:

0.00

AC:

AN:

38906

South Asian (SAS)

AF:

0.00891

AC:

729

AN:

81850

European-Finnish (FIN)

AF:

0.00242

AC:

126

AN:

51964

Middle Eastern (MID)

AF:

0.00157

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00265

AC:

2891

AN:

1091418

Other (OTH)

AF:

0.00282

AC:

167

AN:

59252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

162

324

485

647

809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<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:

0.00169

AC:

258

AN:

152354

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.000601

AC:

AN:

41580

American (AMR)

AF:

0.000458

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00807

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00238

AC:

162

AN:

68036

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.00208

Hom.:

Bravo

AF:

0.00142

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000554

AC:

ESP6500EA

AF:

0.00172

AC:

ExAC

AF:

0.00201

AC:

242

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR3: PP3, BS2

Epileptic encephalopathy

Benign:1

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.010

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

0.69

PhyloP100

8.0

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.45

Sift

Benign

0.14

Polyphen

0.75

Vest4

0.49

MVP

0.43

MPC

0.29

ClinPred

0.027

GERP RS

5.3

Varity_R

0.26

gMVP

0.21

Mutation Taster

=25/75

disease causing

(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