NM_001036.6:c.5299G>A

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.5299G>A(p.Glu1767Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00449 in 1,613,938 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 201 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.51

Publications

5 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=0.002911806).

BP6

Variant 15-33662829-G-A is Benign according to our data. Variant chr15-33662829-G-A is described in ClinVar as Benign. ClinVar VariationId is 461925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.5299G>A	p.Glu1767Lys	missense_variant	Exon 35 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.5299G>A	p.Glu1767Lys	missense_variant	Exon 35 of 104	1	NM_001036.6	ENSP00000489262.1	Q15413-1
RYR3	ENST00000389232.9 link	c.5299G>A	p.Glu1767Lys	missense_variant	Exon 35 of 104	5		ENSP00000373884.5	A0A0X1KG73
RYR3	ENST00000415757.7 link	c.5299G>A	p.Glu1767Lys	missense_variant	Exon 35 of 103	2		ENSP00000399610.3	Q15413-2
RYR3	ENST00000634418.1 link	c.5299G>A	p.Glu1767Lys	missense_variant	Exon 35 of 102	5		ENSP00000489529.1	A0A0U1RRH1

Frequencies

GnomAD3 genomes

AF:

0.00446

AC:

679

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00596

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0679

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00912

AC:

2272

AN:

249228

AF XY:

0.0116

show subpopulations

Gnomad AFR exome

AF:

0.00659

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.000795

Gnomad EAS exome

AF:

0.00167

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000778

Gnomad OTH exome

AF:

0.00512

GnomAD4 exome

AF:

0.00449

AC:

6567

AN:

1461644

Hom.:

201

Cov.:

AF XY:

0.00610

AC XY:

4434

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.00726

AC:

243

AN:

33480

American (AMR)

AF:

0.00226

AC:

101

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000574

AC:

AN:

26136

East Asian (EAS)

AF:

0.000907

AC:

AN:

39700

South Asian (SAS)

AF:

0.0591

AC:

5094

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000542

AC:

603

AN:

1111860

Other (OTH)

AF:

0.00654

AC:

395

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

425

850

1276

1701

2126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<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:

0.00441

AC:

672

AN:

152294

Hom.:

Cov.:

AF XY:

0.00545

AC XY:

406

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00592

AC:

246

AN:

41562

American (AMR)

AF:

0.00183

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00212

AC:

AN:

5190

South Asian (SAS)

AF:

0.0667

AC:

321

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

68024

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00193

Hom.:

Bravo

AF:

0.00279

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00482

AC:

ESP6500EA

AF:

0.000593

AC:

ExAC

AF:

0.0103

AC:

1242

Asia WGS

AF:

0.0440

AC:

153

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Benign:1

Dec 03, 2024

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

0.078

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;.;.;.;.

Eigen

Benign

0.0060

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.80

T;T;T;T;T

MetaRNN

Benign

0.0029

T;T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.8

L;L;.;.;.

PhyloP100

5.5

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.1

.;N;N;.;.

REVEL

Benign

0.10

Sift

Benign

0.32

.;T;T;.;.

Polyphen

0.0

B;B;.;.;.

Vest4

0.41

MPC

0.21

ClinPred

0.017

GERP RS

5.1

Varity_R

0.22

gMVP

0.38

Mutation Taster

=96/4

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