19-38506525-A-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000540.3(RYR1):c.8671A>C(p.Lys2891Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K2891K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 9.27

Publications

5 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09842819).

BP6

Variant 19-38506525-A-C is Benign according to our data. Variant chr19-38506525-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 544391.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.8671A>C	p.Lys2891Gln	missense_variant	Exon 56 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.8671A>C	p.Lys2891Gln	missense_variant	Exon 56 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.000408

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000152

AC:

AN:

250210

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000835

AC:

122

AN:

1461828

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

33478

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000428

AC:

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1111990

Other (OTH)

AF:

0.0000828

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000407

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41530

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000388

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67996

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.000234

Hom.:

Bravo

AF:

0.000434

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000181

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jul 02, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as a secondary finding via exome sequencing in two patients reported to have either developmental delay or chronic constipation (Chetruengchai et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12668474, 34621001) -

Jun 13, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RYR1-related disorder

Uncertain:1Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 05, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RYR1 c.8671A>C variant is predicted to result in the amino acid substitution p.Lys2891Gln. This variant was observed in 2 individuals with RYR1 unrelated conditions and assessed as variant of unknown significance (Chetruengchai et al 2022. PubMed ID: 34621001 STable1). This variant is reported in 0.14% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38997165-A-C). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant hyperthermia, susceptibility to, 1

Benign:1

Jan 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Benign

0.85

DEOGEN2

Uncertain

0.75

.;D

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.098

T;T

MetaSVM

Uncertain

0.66

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

9.3

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.69

Sift

Benign

0.033

D;D

Polyphen

0.99

D;D

Vest4

0.51

MVP

1.0

MPC

0.60

ClinPred

0.14

GERP RS

3.1

Varity_R

0.71

gMVP

0.72

Mutation Taster

=36/64

disease causing

(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