19-38433756-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000540.3(RYR1):​c.-74A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0037 ( 0 hom., cov: 0)
Exomes 𝑓: 0.070 ( 1 hom. )
Failed GnomAD Quality Control

Consequence

RYR1
NM_000540.3 5_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.180
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.49).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RYR1NM_000540.3 linkuse as main transcriptc.-74A>C 5_prime_UTR_variant 1/106 ENST00000359596.8 NP_000531.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.-74A>C 5_prime_UTR_variant 1/1065 NM_000540.3 ENSP00000352608 A2P21817-1
RYR1ENST00000355481.8 linkuse as main transcriptc.-74A>C 5_prime_UTR_variant 1/1051 ENSP00000347667 P4P21817-2

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
60
AN:
15976
Hom.:
0
Cov.:
0
FAILED QC
Gnomad AFR
AF:
0.00363
Gnomad AMI
AF:
0.0152
Gnomad AMR
AF:
0.00264
Gnomad ASJ
AF:
0.00270
Gnomad EAS
AF:
0.00515
Gnomad SAS
AF:
0.00469
Gnomad FIN
AF:
0.00562
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00351
Gnomad OTH
AF:
0.00403
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0702
AC:
7188
AN:
102432
Hom.:
1
Cov.:
0
AF XY:
0.0665
AC XY:
3790
AN XY:
57032
show subpopulations
Gnomad4 AFR exome
AF:
0.0743
Gnomad4 AMR exome
AF:
0.0617
Gnomad4 ASJ exome
AF:
0.0914
Gnomad4 EAS exome
AF:
0.0903
Gnomad4 SAS exome
AF:
0.0353
Gnomad4 FIN exome
AF:
0.0500
Gnomad4 NFE exome
AF:
0.0772
Gnomad4 OTH exome
AF:
0.0956
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00375
AC:
60
AN:
16014
Hom.:
0
Cov.:
0
AF XY:
0.00327
AC XY:
28
AN XY:
8550
show subpopulations
Gnomad4 AFR
AF:
0.00360
Gnomad4 AMR
AF:
0.00263
Gnomad4 ASJ
AF:
0.00270
Gnomad4 EAS
AF:
0.00521
Gnomad4 SAS
AF:
0.00473
Gnomad4 FIN
AF:
0.00562
Gnomad4 NFE
AF:
0.00351
Gnomad4 OTH
AF:
0.00388
Alfa
AF:
0.000253
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Congenital multicore myopathy with external ophthalmoplegia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Central core myopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Neuromuscular disease, congenital, with uniform type 1 fiber Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsDec 14, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.49
CADD
Benign
11
DANN
Benign
0.83

Splicing

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: rs886054375; hg19: chr19-38924396; API