rs201071539
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_201384.3(PLEC):c.2875G>A(p.Gly959Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,599,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 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. G959F) has been classified as Uncertain significance.
Frequency
Consequence
NM_201384.3 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 |
---|---|---|---|---|---|---|---|
PLEC | NM_201384.3 | c.2875G>A | p.Gly959Ser | missense_variant | 23/32 | ENST00000345136.8 | |
PLEC | NM_201378.4 | c.2833G>A | p.Gly945Ser | missense_variant | 23/32 | ENST00000356346.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEC | ENST00000345136.8 | c.2875G>A | p.Gly959Ser | missense_variant | 23/32 | 1 | NM_201384.3 | ||
PLEC | ENST00000356346.7 | c.2833G>A | p.Gly945Ser | missense_variant | 23/32 | 1 | NM_201378.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152244Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000446 AC: 1AN: 224314Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 124804
GnomAD4 exome AF: 0.0000124 AC: 18AN: 1447286Hom.: 0 Cov.: 65 AF XY: 0.0000111 AC XY: 8AN XY: 720488
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152244Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74378
ClinVar
Submissions by phenotype
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 | Nov 27, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 986 of the PLEC protein (p.Gly986Ser). This variant is present in population databases (rs201071539, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with PLEC-related conditions. ClinVar contains an entry for this variant (Variation ID: 471565). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLEC protein function with a negative predictive value of 80%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at