15-33696482-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001036.6(RYR3):c.6125A>G(p.Asn2042Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00105 in 1,613,942 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 3 hom., cov: 31)

Exomes 𝑓: 0.00098 ( 14 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.37

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009640485).

BP6

Variant 15-33696482-A-G is Benign according to our data. Variant chr15-33696482-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 445300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00098 (1432/1461666) while in subpopulation AMR AF= 0.0195 (873/44716). AF 95% confidence interval is 0.0184. There are 14 homozygotes in gnomad4_exome. There are 690 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.6125A>G	p.Asn2042Ser	missense_variant	Exon 39 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.6125A>G	p.Asn2042Ser	missense_variant	Exon 39 of 104	1	NM_001036.6	ENSP00000489262.1		Q15413-1

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

256

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00623

GnomAD3 exomes

AF:

0.00342

AC:

849

AN:

248334

Hom.:

AF XY:

0.00276

AC XY:

372

AN XY:

134754

show subpopulations

Gnomad AFR exome

AF:

0.000775

Gnomad AMR exome

AF:

0.0196

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00122

Gnomad SAS exome

AF:

0.00402

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000446

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.000980

AC:

1432

AN:

1461666

Hom.:

Cov.:

AF XY:

0.000949

AC XY:

690

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.0195

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000756

Gnomad4 SAS exome

AF:

0.00413

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000729

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.00167

AC:

255

AN:

152276

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.0122

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.000343

Hom.:

Bravo

AF:

0.00309

ESP6500AA

AF:

0.000969

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00286

AC:

346

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/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

- -

Jun 16, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epileptic encephalopathy

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;.;.;.;.

Eigen

Benign

-0.00017

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;D;D;D;D

MetaRNN

Benign

0.0096

T;T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.2

L;L;.;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.6

.;N;N;.;.

REVEL

Benign

0.098

Sift

Uncertain

0.026

.;D;D;.;.

Polyphen

0.26

B;B;.;.;.

Vest4

0.39

MVP

0.66

MPC

0.18

ClinPred

0.012

GERP RS

4.8

Varity_R

0.18

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over