rs181264765

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.6617A>C(p.Asn2206Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,613,910 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 21 hom. )

Consequence

RYR3
NM_001036.6 missense, splice_region

Scores

Splicing: ADA: 0.8759

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 9.22

Publications

9 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=0.034886897).

BP6

Variant 15-33707052-A-C is Benign according to our data. Variant chr15-33707052-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 461936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.6617A>C	p.Asn2206Thr	missense_variant, splice_region_variant	Exon 43 of 104	ENST00000634891.2	NP_001027.3	Q15413-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR3	ENST00000634891.2 link	c.6617A>C	p.Asn2206Thr	missense_variant, splice_region_variant	Exon 43 of 104	1	NM_001036.6	ENSP00000489262.1	Q15413-1
RYR3	ENST00000389232.9 link	c.6617A>C	p.Asn2206Thr	missense_variant, splice_region_variant	Exon 43 of 104	5		ENSP00000373884.5	A0A0X1KG73
RYR3	ENST00000415757.7 link	c.6617A>C	p.Asn2206Thr	missense_variant, splice_region_variant	Exon 43 of 103	2		ENSP00000399610.3	Q15413-2
RYR3	ENST00000634418.1 link	c.6617A>C	p.Asn2206Thr	missense_variant, splice_region_variant	Exon 43 of 102	5		ENSP00000489529.1	A0A0U1RRH1

Frequencies

GnomAD3 genomes

AF:

0.00154

AC:

235

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00226

AC:

562

AN:

249044

AF XY:

0.00246

show subpopulations

Gnomad AFR exome

AF:

0.000452

Gnomad AMR exome

AF:

0.000870

Gnomad ASJ exome

AF:

0.00388

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00229

Gnomad OTH exome

AF:

0.00248

GnomAD4 exome

AF:

0.00303

AC:

4430

AN:

1461582

Hom.:

Cov.:

AF XY:

0.00315

AC XY:

2288

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

33474

American (AMR)

AF:

0.000962

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00367

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00627

AC:

541

AN:

86244

European-Finnish (FIN)

AF:

0.000281

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00316

AC:

3512

AN:

1111802

Other (OTH)

AF:

0.00310

AC:

187

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

218

436

653

871

1089

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00154

AC:

235

AN:

152328

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41568

American (AMR)

AF:

0.00157

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00373

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00240

AC:

163

AN:

68034

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00241

Hom.:

Bravo

AF:

0.00172

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00283

AC:

ExAC

AF:

0.00208

AC:

252

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00267

EpiControl

AF:

0.00267

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Uncertain significance and reported on 03-08-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR3: BS2 -

Epileptic encephalopathy

Benign:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RYR3-related disorder

Benign:1

Jul 01, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.;.;.;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.035

T;T;T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

M;M;.;.;.

PhyloP100

9.2

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.3

.;D;D;.;.

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

.;D;D;.;.

Polyphen

1.0

D;D;.;.;.

Vest4

0.78

MVP

0.94

MPC

0.70

ClinPred

0.021

GERP RS

5.3

Varity_R

0.79

gMVP

0.75

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.88

dbscSNV1_RF

Benign

0.71

SpliceAI score (max)

0.040

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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rs181264765

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