rs782733657
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_201384.3(PLEC):c.9823C>T(p.Arg3275Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3275H) has been classified as Uncertain significance.
Frequency
Consequence
NM_201384.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEC | NM_201384.3 | c.9823C>T | p.Arg3275Cys | missense_variant | 32/32 | ENST00000345136.8 | |
PLEC | NM_201378.4 | c.9781C>T | p.Arg3261Cys | missense_variant | 32/32 | ENST00000356346.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEC | ENST00000345136.8 | c.9823C>T | p.Arg3275Cys | missense_variant | 32/32 | 1 | NM_201384.3 | ||
PLEC | ENST00000356346.7 | c.9781C>T | p.Arg3261Cys | missense_variant | 32/32 | 1 | NM_201378.4 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249044Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135320
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1460940Hom.: 0 Cov.: 72 AF XY: 0.0000261 AC XY: 19AN XY: 726786
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74362
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 11, 2017 | The R3302C variant in the PLEC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R3302C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R3302C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R3302C as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 05, 2020 | - - |
Epidermolysis bullosa simplex, Ogna type;C2677349:Epidermolysis bullosa simplex 5C, with pyloric atresia;C2931072:Epidermolysis bullosa simplex 5B, with muscular dystrophy;C3150989:Autosomal recessive limb-girdle muscular dystrophy type 2Q;C4225309:Epidermolysis bullosa simplex with nail dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 16, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 423095). This variant has not been reported in the literature in individuals affected with PLEC-related conditions. This variant is present in population databases (rs782733657, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3302 of the PLEC protein (p.Arg3302Cys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at