rs61996335

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000634891.2(RYR3):c.9254C>G(p.Pro3085Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00399 in 1,613,820 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 18 hom. )

Consequence

RYR3
ENST00000634891.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 6.11

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010045499).

BP6

Variant 15-33780327-C-G is Benign according to our data. Variant chr15-33780327-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461984.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR3	NM_001036.6 linkuse as main transcript	c.9254C>G	p.Pro3085Arg	missense_variant	65/104	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.9254C>G	p.Pro3085Arg	missense_variant	65/104	1	NM_001036.6	ENSP00000489262	P4	Q15413-1

Frequencies

GnomAD3 genomes

AF:

0.00298

AC:

453

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00433

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00547

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00281

AC:

699

AN:

248350

Hom.:

AF XY:

0.00284

AC XY:

382

AN XY:

134726

show subpopulations

Gnomad AFR exome

AF:

0.000712

Gnomad AMR exome

AF:

0.000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00180

Gnomad FIN exome

AF:

0.00367

Gnomad NFE exome

AF:

0.00461

Gnomad OTH exome

AF:

0.00265

GnomAD4 exome

AF:

0.00409

AC:

5979

AN:

1461504

Hom.:

Cov.:

AF XY:

0.00398

AC XY:

2893

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00173

Gnomad4 FIN exome

AF:

0.00425

Gnomad4 NFE exome

AF:

0.00477

Gnomad4 OTH exome

AF:

0.00412

GnomAD4 genome

AF:

0.00297

AC:

453

AN:

152316

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

190

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00433

Gnomad4 NFE

AF:

0.00547

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00434

Hom.:

Bravo

AF:

0.00258

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.000514

AC:

ESP6500EA

AF:

0.00350

AC:

ExAC

AF:

0.00277

AC:

335

EpiCase

AF:

0.00425

EpiControl

AF:

0.00427

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	RYR3: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jan 12, 2022	RYR3 NM_001036.4 exon 65 p.Pro3085Arg (c.9254C>G): This variant has not been reported in the literature but is present in 0.5% (372/68026) of European alleles including 3 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-33780327-C-G?dataset=gnomad_r3). This variant is present in ClinVar classified as a benign variant (Variation ID:461984). Evolutionary conservation suggests that this variant may not impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore, the clinical significance of this variant is uncertain. -

Epileptic encephalopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

- -

RYR3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2021

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

Benign

0.14

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.65

D;.;.;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.010

T;T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.2

M;M;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.2

.;D;.;.;.

REVEL

Benign

0.27

Sift

Benign

0.36

.;T;.;.;.

Polyphen

0.29

B;B;.;.;.

Vest4

0.46

MVP

0.29

MPC

0.24

ClinPred

0.035

GERP RS

5.5

Varity_R

0.25

gMVP

0.30

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

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