rs181264765

Positions:

chr15-33707052-A-C

Variant summary

Our verdict is Benign. Variant got -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

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 -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. Variant chr15-33707052-A-C is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR3	NM_001036.6 linkuse as main transcript	c.6617A>C	p.Asn2206Thr	missense_variant, splice_region_variant	43/104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2 linkuse as main transcript	c.6617A>C	p.Asn2206Thr	missense_variant, splice_region_variant	43/104	1	NM_001036.6	ENSP00000489262	P4	Q15413-1
RYR3	ENST00000389232.9 linkuse as main transcript	c.6617A>C	p.Asn2206Thr	missense_variant, splice_region_variant	43/104	5		ENSP00000373884	A1
RYR3	ENST00000415757.7 linkuse as main transcript	c.6617A>C	p.Asn2206Thr	missense_variant, splice_region_variant	43/103	2		ENSP00000399610	A2	Q15413-2
RYR3	ENST00000634418.1 linkuse as main transcript	c.6617A>C	p.Asn2206Thr	missense_variant, splice_region_variant	43/102	5		ENSP00000489529

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

GnomAD3 exomes

AF:

0.00226

AC:

562

AN:

249044

Hom.:

AF XY:

0.00246

AC XY:

333

AN XY:

135108

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 SAS exome

AF:

0.00680

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

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.000962

Gnomad4 ASJ exome

AF:

0.00367

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00627

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.00316

Gnomad4 OTH exome

AF:

0.00310

GnomAD4 genome

AF:

0.00154

AC:

235

AN:

152328

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00240

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00253

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

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	RYR3: BS2 -

Epileptic encephalopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 15, 2023

- -

RYR3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

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

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;.;.;.

MutationTaster

Benign

1.0

D;D

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

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

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