rs61996336

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001036.6(RYR3):c.9816C>T(p.Tyr3272Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0243 in 1,613,704 control chromosomes in the GnomAD database, including 608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 39 hom., cov: 33)

Exomes 𝑓: 0.025 ( 569 hom. )

Consequence

RYR3
NM_001036.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.16

Publications

2 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 15-33788444-C-T is Benign according to our data. Variant chr15-33788444-C-T is described in ClinVar as Benign. ClinVar VariationId is 461991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.16 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0171 (2609/152322) while in subpopulation NFE AF = 0.0289 (1966/68028). AF 95% confidence interval is 0.0278. There are 39 homozygotes in GnomAd4. There are 1198 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 39 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.9816C>T	p.Tyr3272Tyr	synonymous_variant	Exon 67 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.9816C>T	p.Tyr3272Tyr	synonymous_variant	Exon 67 of 104	1	NM_001036.6	ENSP00000489262.1		Q15413-1

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2611

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00521

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0130

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00787

Gnomad FIN

AF:

0.00857

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0289

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.0156

AC:

3870

AN:

248424

AF XY:

0.0157

show subpopulations

Gnomad AFR exome

AF:

0.00452

Gnomad AMR exome

AF:

0.0105

Gnomad ASJ exome

AF:

0.0196

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.00832

Gnomad NFE exome

AF:

0.0246

Gnomad OTH exome

AF:

0.0202

GnomAD4 exome

AF:

0.0250

AC:

36535

AN:

1461382

Hom.:

569

Cov.:

AF XY:

0.0245

AC XY:

17794

AN XY:

726952

show subpopulations

African (AFR)

AF:

0.00382

AC:

128

AN:

33466

American (AMR)

AF:

0.0109

AC:

486

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0191

AC:

499

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39692

South Asian (SAS)

AF:

0.00643

AC:

555

AN:

86250

European-Finnish (FIN)

AF:

0.00888

AC:

474

AN:

53398

Middle Eastern (MID)

AF:

0.0127

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0297

AC:

33007

AN:

1111606

Other (OTH)

AF:

0.0217

AC:

1307

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1741

3481

5222

6962

8703

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1254

2508

3762

5016

6270

<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:

0.0171

AC:

2609

AN:

152322

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1198

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00517

AC:

215

AN:

41572

American (AMR)

AF:

0.0129

AC:

198

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00787

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00857

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0289

AC:

1966

AN:

68028

Other (OTH)

AF:

0.0184

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

133

266

400

533

666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0222

Hom.:

Bravo

AF:

0.0167

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0273

EpiControl

AF:

0.0256

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Benign:1

Jan 13, 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

- -

RYR3-related disorder

Benign:1

Jul 13, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

1.1

(source)

DANN

Benign

0.48

PhyloP100

-1.2

Mutation Taster

=100/0

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

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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