rs863225011
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000357033.9(DMD):c.8038C>T(p.Arg2680Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R2680R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000357033.9 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DMD | NM_004006.3 | c.8038C>T | p.Arg2680Ter | stop_gained | 55/79 | ENST00000357033.9 | NP_003997.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.8038C>T | p.Arg2680Ter | stop_gained | 55/79 | 1 | NM_004006.3 | ENSP00000354923 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 111035Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33271 FAILED QC
GnomAD4 exome Cov.: 30
GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 111035Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33271
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 20, 2018 | The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 13, 2022 | - - |
Duchenne muscular dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | This sequence change creates a premature translational stop signal at codon 2680 (p.Arg2680*) of the DMD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DMD are known to be pathogenic (Aartsma‐Rus et al). This variant has been reported in individuals affected with Duchenne muscular dystrophy (DMD) (Magri, Francesca, et al,Tuffery-Giraud, Sylvie, et al). This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change in DMD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. For these reasons, this variant has been classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 10, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 217213). This premature translational stop signal has been observed in individuals with Duchenne muscular dystrophy (DMD) (PMID: 15351422, 16770791, 17041906, 18583217, 19835634, 19937601, 21396098, 25612904, 25636106). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2680*) in the DMD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DMD are known to be pathogenic (PMID: 16770791, 25007885). - |
Qualitative or quantitative defects of dystrophin Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 17, 2019 | Variant summary: DMD c.8038C>T (p.Arg2680X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Large deletions downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 174421 control chromosomes. c.8038C>T has been reported in the literature in multiple individuals affected with Duchenne muscular dystrophy (eg. Tuffery-Giraud_2004, Flanigan_2011, Magri_2011, Connolly_2015, Ma_2018, Xu_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at