chr19-38463527-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000540.3(RYR1):​c.2682G>C​(p.Pro894Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Consequence

RYR1
NM_000540.3 splice_region, synonymous

Scores

2
Splicing: ADA: 1.000
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.276
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR1NM_000540.3 linkc.2682G>C p.Pro894Pro splice_region_variant, synonymous_variant Exon 21 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.2682G>C p.Pro894Pro splice_region_variant, synonymous_variant Exon 21 of 106 5 NM_000540.3 ENSP00000352608.2 P21817-1
RYR1ENST00000355481.8 linkc.2682G>C p.Pro894Pro splice_region_variant, synonymous_variant Exon 21 of 105 1 ENSP00000347667.3 P21817-2
RYR1ENST00000599547.6 linkn.2682G>C splice_region_variant, non_coding_transcript_exon_variant Exon 21 of 80 2 ENSP00000471601.2 M0R127

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Congenital multicore myopathy with external ophthalmoplegia;C5830701:Central core myopathy Uncertain:1
-
Suma Genomics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.41
CADD
Benign
22
DANN
Benign
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.97
SpliceAI score (max)
0.80
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.26
Position offset: 44
DS_DL_spliceai
0.80
Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-38954167; COSMIC: COSV62089204; COSMIC: COSV62089204; API