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rs775442275

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6BP7

The NM_000540.3(RYR1):​c.2937G>A​(p.Ala979=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,613,144 control chromosomes in the GnomAD database, including 1 homozygotes. 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. A979A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000062 ( 1 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: -3.03
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
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.4).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-38466157-G-A is Benign according to our data. Variant chr19-38466157-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 329003.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-3.03 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RYR1NM_000540.3 linkuse as main transcriptc.2937G>A p.Ala979= synonymous_variant 24/106 ENST00000359596.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.2937G>A p.Ala979= synonymous_variant 24/1065 NM_000540.3 A2P21817-1
RYR1ENST00000355481.8 linkuse as main transcriptc.2937G>A p.Ala979= synonymous_variant 24/1051 P4P21817-2
RYR1ENST00000594111.1 linkuse as main transcriptn.30G>A non_coding_transcript_exon_variant 1/22
RYR1ENST00000599547.6 linkuse as main transcriptc.2937G>A p.Ala979= synonymous_variant, NMD_transcript_variant 24/802

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000329
AC:
5
AN:
152154
Hom.:
0
Cov.:
32
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:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000485
AC:
12
AN:
247260
Hom.:
1
AF XY:
0.0000745
AC XY:
10
AN XY:
134186
show subpopulations
Gnomad AFR exome
AF:
0.0000629
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.0000999
Gnomad EAS exome
AF:
0.0000549
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000359
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000616
AC:
90
AN:
1460990
Hom.:
1
Cov.:
30
AF XY:
0.0000537
AC XY:
39
AN XY:
726808
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000928
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000567
Gnomad4 OTH exome
AF:
0.000232
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000329
AC:
5
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000283
Hom.:
0
Bravo
AF:
0.0000491
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthDec 18, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 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. -
RYR1-related disorder Benign:2
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 17, 2024- -
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesApr 09, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Congenital multicore myopathy with external ophthalmoplegia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 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, IlluminaJan 13, 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- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.40
CADD
Benign
0.15
DANN
Benign
0.93

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: rs775442275; hg19: chr19-38956797; API