rs76537615

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000540.3(RYR1):​c.4894C>T​(p.Pro1632Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,562,580 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0054 ( 3 hom., cov: 32)
Exomes 𝑓: 0.00057 ( 5 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

5
8
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 7.83
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 -12 ACMG points.

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=0.01128754).
BP6
Variant 19-38483476-C-T is Benign according to our data. Variant chr19-38483476-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159852.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=6, Uncertain_significance=1}. Variant chr19-38483476-C-T is described in Lovd as [Likely_benign]. Variant chr19-38483476-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00539 (820/152208) while in subpopulation AFR AF= 0.0185 (769/41502). AF 95% confidence interval is 0.0174. There are 3 homozygotes in gnomad4. There are 389 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RYR1NM_000540.3 linkuse as main transcriptc.4894C>T p.Pro1632Ser missense_variant 33/106 ENST00000359596.8 NP_000531.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.4894C>T p.Pro1632Ser missense_variant 33/1065 NM_000540.3 ENSP00000352608 A2P21817-1
RYR1ENST00000355481.8 linkuse as main transcriptc.4894C>T p.Pro1632Ser missense_variant 33/1051 ENSP00000347667 P4P21817-2
RYR1ENST00000599547.6 linkuse as main transcriptc.4894C>T p.Pro1632Ser missense_variant, NMD_transcript_variant 33/802 ENSP00000471601

Frequencies

GnomAD3 genomes
AF:
0.00538
AC:
819
AN:
152090
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0185
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00249
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00103
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00431
GnomAD3 exomes
AF:
0.00125
AC:
213
AN:
169838
Hom.:
1
AF XY:
0.000830
AC XY:
76
AN XY:
91542
show subpopulations
Gnomad AFR exome
AF:
0.0191
Gnomad AMR exome
AF:
0.000726
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000766
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000140
Gnomad OTH exome
AF:
0.000428
GnomAD4 exome
AF:
0.000574
AC:
810
AN:
1410372
Hom.:
5
Cov.:
32
AF XY:
0.000460
AC XY:
321
AN XY:
697634
show subpopulations
Gnomad4 AFR exome
AF:
0.0212
Gnomad4 AMR exome
AF:
0.000856
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000870
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000459
Gnomad4 OTH exome
AF:
0.00128
GnomAD4 genome
AF:
0.00539
AC:
820
AN:
152208
Hom.:
3
Cov.:
32
AF XY:
0.00523
AC XY:
389
AN XY:
74430
show subpopulations
Gnomad4 AFR
AF:
0.0185
Gnomad4 AMR
AF:
0.00248
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000828
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00426
Alfa
AF:
0.000459
Hom.:
1
Bravo
AF:
0.00603
ESP6500AA
AF:
0.0168
AC:
73
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00111
AC:
131
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:11
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:3
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-- -
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 16, 2018This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 10, 2016- -
not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingAthena DiagnosticsNov 04, 2019- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Malignant hypothermia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaSep 24, 2015- -
RYR1-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Malignant hyperthermia of anesthesia Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Multiminicore myopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Central core myopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Uncertain
-0.020
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.77
.;D
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.89
D;D
MetaRNN
Benign
0.011
T;T
MetaSVM
Uncertain
0.75
D
MutationAssessor
Uncertain
2.5
M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-6.6
D;D
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0030
D;D
Polyphen
1.0
D;D
Vest4
0.73
MVP
0.99
MPC
1.0
ClinPred
0.046
T
GERP RS
5.0
Varity_R
0.64
gMVP
0.78

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: rs76537615; hg19: chr19-38974116; API