rs755065800

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000540.3(RYR1):c.12869C>T(p.Ala4290Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000676 in 1,005,642 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 2 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.397

Publications

1 publications found

Variant links:

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

RYR1 Gene-Disease associations (from GenCC):

malignant hyperthermia, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
congenital multicore myopathy with external ophthalmoplegia
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
RYR1-related myopathy
Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
central core myopathy
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
King-Denborough syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
malignant hyperthermia of anesthesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive centronuclear myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
benign Samaritan congenital myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital myopathy with myasthenic-like onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
lethal multiple pterygium syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0445036).

BP6

Variant 19-38565203-C-T is Benign according to our data. Variant chr19-38565203-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 544505.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00271 (397/146552) while in subpopulation AFR AF = 0.00909 (372/40902). AF 95% confidence interval is 0.00833. There are 1 homozygotes in GnomAd4. There are 198 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.12869C>T	p.Ala4290Val	missense_variant	Exon 91 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.12869C>T	p.Ala4290Val	missense_variant	Exon 91 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.00270

AC:

396

AN:

146446

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00910

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000814

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000831

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000759

Gnomad OTH

AF:

0.00199

GnomAD2 exomes

AF:

0.00

AC:

AN:

550

AF XY:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000329

AC:

283

AN:

859090

Hom.:

Cov.:

AF XY:

0.000338

AC XY:

135

AN XY:

399468

show subpopulations

African (AFR)

AF:

0.0106

AC:

173

AN:

16292

American (AMR)

AF:

0.00107

AC:

AN:

1862

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5766

East Asian (EAS)

AF:

0.00

AC:

AN:

4726

South Asian (SAS)

AF:

0.000913

AC:

AN:

17530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3262

Middle Eastern (MID)

AF:

0.00400

AC:

AN:

1748

European-Non Finnish (NFE)

AF:

0.0000744

AC:

AN:

779154

Other (OTH)

AF:

0.000939

AC:

AN:

28750

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00271

AC:

397

AN:

146552

Hom.:

Cov.:

AF XY:

0.00277

AC XY:

198

AN XY:

71354

show subpopulations

African (AFR)

AF:

0.00909

AC:

372

AN:

40902

American (AMR)

AF:

0.000813

AC:

AN:

14756

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3394

East Asian (EAS)

AF:

0.00

AC:

AN:

5088

South Asian (SAS)

AF:

0.000831

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0000759

AC:

AN:

65884

Other (OTH)

AF:

0.00197

AC:

AN:

2034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00214

Hom.:

ExAC

AF:

0.00255

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

RYR1-related disorder

Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 06, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy

Uncertain:1

Dec 08, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR1: PP3, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.31

.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.26

T;T

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.045

T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

0.69

.;N

PhyloP100

0.40

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.21

N;N

REVEL

Benign

0.27

Sift

Benign

0.62

T;T

Polyphen

0.39

B;B

Vest4

0.15

MutPred

0.33

.;Gain of MoRF binding (P = 0.0714);

MVP

0.82

MPC

0.73

ClinPred

0.070

GERP RS

-2.3

PromoterAI

-0.037

Neutral

(source)

Varity_R

0.072

gMVP

0.32

Mutation Taster

=63/37

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