rs182004703

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM5PP2BP4_StrongBP6_Moderate

The NM_000540.3(RYR1):c.4026C>A(p.Ser1342Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,560,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1342G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.42

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-38473635-A-G is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR1. . Gene score misZ 1.918 (greater than the threshold 3.09). Trascript score misZ 3.9788 (greater than threshold 3.09). GenCC has associacion of gene with King-Denborough syndrome, congenital multicore myopathy with external ophthalmoplegia, autosomal recessive centronuclear myopathy, RYR1-related myopathy, lethal multiple pterygium syndrome, malignant hyperthermia of anesthesia, benign Samaritan congenital myopathy, malignant hyperthermia, susceptibility to, 1, congenital myopathy with myasthenic-like onset, central core myopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.008480877).

BP6

Variant 19-38473637-C-A is Benign according to our data. Variant chr19-38473637-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 478226.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.4026C>A	p.Ser1342Arg	missense_variant	28/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.4026C>A	p.Ser1342Arg	missense_variant	28/106	5	NM_000540.3	ENSP00000352608	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.4026C>A	p.Ser1342Arg	missense_variant	28/105	1		ENSP00000347667	P4	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	c.4026C>A	p.Ser1342Arg	missense_variant, NMD_transcript_variant	28/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.000459

AC:

AN:

159194

Hom.:

AF XY:

0.000466

AC XY:

AN XY:

85822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000401

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000422

Gnomad FIN exome

AF:

0.00248

Gnomad NFE exome

AF:

0.000456

Gnomad OTH exome

AF:

0.000887

GnomAD4 exome

AF:

0.000326

AC:

459

AN:

1408318

Hom.:

Cov.:

AF XY:

0.000305

AC XY:

212

AN XY:

695656

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000124

Gnomad4 FIN exome

AF:

0.00362

Gnomad4 NFE exome

AF:

0.000239

Gnomad4 OTH exome

AF:

0.000360

GnomAD4 genome

AF:

0.000296

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00189

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.000950

Alfa

AF:

0.000201

Hom.:

Bravo

AF:

0.000193

ExAC

AF:

0.000555

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

RYR1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.34

CADD

Benign

0.078

DANN

Benign

0.83

DEOGEN2

Benign

0.37

.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.54

T;T

MetaRNN

Benign

0.0085

T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

-0.34

N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.23

Sift

Benign

0.54

T;T

Polyphen

0.0010

B;B

Vest4

0.15

MutPred

0.39

Gain of MoRF binding (P = 0.0104);Gain of MoRF binding (P = 0.0104);

MVP

0.58

MPC

0.59

ClinPred

0.018

GERP RS

-7.9

Varity_R

0.057

gMVP

0.22

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