chr19-38565241-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000540.3(RYR1):c.12907C>T(p.Arg4303Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 146,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4303G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.372

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26440454).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.12907C>T	p.Arg4303Trp	missense	Exon 91 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.12892C>T	p.Arg4298Trp	missense	Exon 90 of 105	NP_001036188.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.12907C>T	p.Arg4303Trp	missense	Exon 91 of 106	ENSP00000352608.2
RYR1	ENST00000355481.8	TSL:1	c.12892C>T	p.Arg4298Trp	missense	Exon 90 of 105	ENSP00000347667.3
RYR1	ENST00000594335.6	TSL:1	n.*3617C>T		non_coding_transcript_exon	Exon 88 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes

AF:

0.00000685

AC:

AN:

146082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000152

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

843196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

390564

African (AFR)

AF:

0.00

AC:

AN:

15946

American (AMR)

AF:

0.00

AC:

AN:

1354

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5356

East Asian (EAS)

AF:

0.00

AC:

AN:

3934

South Asian (SAS)

AF:

0.00

AC:

AN:

17380

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1642

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

768436

Other (OTH)

AF:

0.00

AC:

AN:

27864

GnomAD4 genome

AF:

0.00000685

AC:

AN:

146082

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

71048

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40754

American (AMR)

AF:

0.00

AC:

AN:

14702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3390

East Asian (EAS)

AF:

0.00

AC:

AN:

5104

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000152

AC:

AN:

65750

Other (OTH)

AF:

0.00

AC:

AN:

2010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)

RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.59

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.68

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.26

MetaSVM

Uncertain

-0.093

MutationAssessor

Benign

0.0

PhyloP100

0.37

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.8

REVEL

Benign

0.28

Sift

Benign

0.18

Polyphen

0.0020

Vest4

0.20

MutPred

0.50

Loss of methylation at R4303 (P = 0.003)

MVP

0.91

MPC

0.60

ClinPred

0.24

GERP RS

-0.21

PromoterAI

-0.0059

Neutral

(source)

Varity_R

0.047

gMVP

0.36

Mutation Taster

=87/13

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over