rs61996338

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001036.6(RYR3):c.9686C>T(p.Thr3229Met) variant causes a missense change. The variant allele was found at a frequency of 0.00309 in 1,613,936 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 41 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 54 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.10

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=0.0032494962).

BP6

Variant 15-33788314-C-T is Benign according to our data. Variant chr15-33788314-C-T is described in ClinVar as Benign. ClinVar VariationId is 461988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1994/152250) while in subpopulation AFR AF = 0.0427 (1772/41542). AF 95% confidence interval is 0.041. There are 41 homozygotes in GnomAd4. There are 913 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 41 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.9686C>T	p.Thr3229Met	missense_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.9686C>T	p.Thr3229Met	missense_variant	Exon 67 of 104	1	NM_001036.6	ENSP00000489262.1		Q15413-1

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1991

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0427

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00904

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00425

AC:

1058

AN:

249054

AF XY:

0.00335

show subpopulations

Gnomad AFR exome

AF:

0.0446

Gnomad AMR exome

AF:

0.00663

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000807

Gnomad OTH exome

AF:

0.00628

GnomAD4 exome

AF:

0.00205

AC:

2990

AN:

1461686

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

1400

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.0462

AC:

1546

AN:

33480

American (AMR)

AF:

0.00729

AC:

326

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000162

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000674

AC:

749

AN:

1111852

Other (OTH)

AF:

0.00475

AC:

287

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

175

351

526

702

877

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.0131

AC:

1994

AN:

152250

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

913

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0427

AC:

1772

AN:

41542

American (AMR)

AF:

0.00903

AC:

138

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000623

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68020

Other (OTH)

AF:

0.0104

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

192

287

383

479

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:

0.00580

Hom.:

Bravo

AF:

0.0156

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.0401

AC:

164

ESP6500EA

AF:

0.000477

AC:

ExAC

AF:

0.00476

AC:

576

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000818

EpiControl

AF:

0.00154

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Benign:1

Nov 26, 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

0.080

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.25

T;.;.;.;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.97

D;D;D;D;D

MetaRNN

Benign

0.0032

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.1

N;N;.;.;.

PhyloP100

5.1

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.43

.;N;.;.;.

REVEL

Benign

0.14

Sift

Benign

0.42

.;T;.;.;.

Polyphen

0.46

P;P;.;.;.

Vest4

0.31

MVP

0.41

MPC

0.21

ClinPred

0.024

GERP RS

2.4

Varity_R

0.017

gMVP

0.37

Mutation Taster

=69/31

polymorphism

(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