rs193922857

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_000540.3(RYR1):​c.13254C>A​(p.Gly4418Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000084 in 1,463,440 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: -1.29
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BP6
Variant 19-38565588-C-A is Benign according to our data. Variant chr19-38565588-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 133047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38565588-C-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.29 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RYR1NM_000540.3 linkuse as main transcriptc.13254C>A p.Gly4418Gly synonymous_variant 91/106 ENST00000359596.8 NP_000531.2 P21817-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.13254C>A p.Gly4418Gly synonymous_variant 91/1065 NM_000540.3 ENSP00000352608.2 P21817-1

Frequencies

GnomAD3 genomes
AF:
0.000165
AC:
25
AN:
151948
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000508
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000716
AC:
5
AN:
69878
Hom.:
0
AF XY:
0.0000751
AC XY:
3
AN XY:
39972
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000114
Gnomad OTH exome
AF:
0.000963
GnomAD4 exome
AF:
0.0000747
AC:
98
AN:
1311380
Hom.:
0
Cov.:
31
AF XY:
0.0000899
AC XY:
58
AN XY:
645372
show subpopulations
Gnomad4 AFR exome
AF:
0.000300
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000308
Gnomad4 NFE exome
AF:
0.0000802
Gnomad4 OTH exome
AF:
0.0000734
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152060
Hom.:
0
Cov.:
31
AF XY:
0.000215
AC XY:
16
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.000506
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000234

ClinVar

Significance: Likely benign
Submissions summary: Benign:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1Other:1
not provided, no classification providedliterature onlyLeiden Muscular Dystrophy (RYR1)-- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 25, 2021This variant is associated with the following publications: (PMID: 16917943) -
RYR1-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 15, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.55
CADD
Benign
4.2
DANN
Benign
0.89

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.

Other links and lift over

dbSNP: rs193922857; hg19: chr19-39056228; API