rs199986217
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6BS2_Supporting
The NM_004006.3(DMD):c.2827C>T(p.Arg943Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,208,551 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 65 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R943H) has been classified as Likely benign.
Frequency
Consequence
NM_004006.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DMD | NM_004006.3 | c.2827C>T | p.Arg943Cys | missense_variant | 22/79 | ENST00000357033.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.2827C>T | p.Arg943Cys | missense_variant | 22/79 | 1 | NM_004006.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000216 AC: 24AN: 111242Hom.: 0 Cov.: 23 AF XY: 0.0000598 AC XY: 2AN XY: 33458
GnomAD3 exomes AF: 0.000191 AC: 35AN: 182873Hom.: 0 AF XY: 0.000222 AC XY: 15AN XY: 67467
GnomAD4 exome AF: 0.000185 AC: 203AN: 1097253Hom.: 0 Cov.: 30 AF XY: 0.000174 AC XY: 63AN XY: 362727
GnomAD4 genome ? AF: 0.000216 AC: 24AN: 111298Hom.: 0 Cov.: 23 AF XY: 0.0000597 AC XY: 2AN XY: 33524
ClinVar
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 31, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 15, 2019 | Variant summary: DMD c.2827C>T (p.Arg943Cys) results in a non-conservative amino acid change located in the Spectrin/alpha-actinin repeat of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 199644 control chromosomes, including 14 hemizygotes (gnomAD). The high occurrence in hemizygous control individuals suggests this variant is benign. DMD gene is found to be tolerant to missense changes (Z = -4.82, ExAC) providing further evidence in support of a benign role for the variant. c.2827C>T has been reported in the literature in individuals affected with Stargardt macular dystrophy and dilated cardiomyopathy (Haas_2015, Zaneveld_2015). These reports do not provide unequivocal conclusions about association of the variant with Dystrophiopathies. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (3x) and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 09, 2019 | This variant is associated with the following publications: (PMID: 25474345, 25231023) - |
Duchenne muscular dystrophy Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Dilated cardiomyopathy 3B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 01, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 15, 2017 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 27, 2017 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at