19-38494624-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_000540.3(RYR1):​c.6547G>C​(p.Gly2183Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense, splice_region

Scores

11
5
2
Splicing: ADA: 0.8033
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.94
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 Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the RYR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 94 curated benign missense variants. Gene score misZ: 1.918 (below the threshold of 3.09). Trascript score misZ: 3.9788 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR1NM_000540.3 linkc.6547G>C p.Gly2183Arg missense_variant, splice_region_variant Exon 39 of 106 ENST00000359596.8 NP_000531.2 P21817-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RYR1ENST00000359596.8 linkc.6547G>C p.Gly2183Arg missense_variant, splice_region_variant Exon 39 of 106 5 NM_000540.3 ENSP00000352608.2 P21817-1
RYR1ENST00000355481.8 linkc.6547G>C p.Gly2183Arg missense_variant, splice_region_variant Exon 39 of 105 1 ENSP00000347667.3 P21817-2
RYR1ENST00000599547.6 linkn.6547G>C splice_region_variant, non_coding_transcript_exon_variant Exon 39 of 80 2 ENSP00000471601.2 M0R127

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249232
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135122
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:
0.00000895
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461732
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727166
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
31
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.92
.;D
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Uncertain
2.3
M;M
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-7.1
D;D
REVEL
Pathogenic
0.76
Sift
Benign
0.054
T;T
Polyphen
1.0
D;B
Vest4
0.88
MutPred
0.57
Gain of MoRF binding (P = 0.0142);Gain of MoRF binding (P = 0.0142);
MVP
0.99
MPC
0.55
ClinPred
0.96
D
GERP RS
4.4
Varity_R
0.74
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.80
dbscSNV1_RF
Benign
0.54
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: rs774275648; hg19: chr19-38985264; API