rs529986115
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_201384.3(PLEC):c.3176C>T(p.Ala1059Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000619 in 1,599,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. A1059E) 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.3176C>T | p.Ala1059Val | missense_variant | 25/32 | ENST00000345136.8 | |
PLEC | NM_201378.4 | c.3134C>T | p.Ala1045Val | missense_variant | 25/32 | ENST00000356346.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEC | ENST00000345136.8 | c.3176C>T | p.Ala1059Val | missense_variant | 25/32 | 1 | NM_201384.3 | ||
PLEC | ENST00000356346.7 | c.3134C>T | p.Ala1045Val | missense_variant | 25/32 | 1 | NM_201378.4 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152244Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000777 AC: 17AN: 218726Hom.: 0 AF XY: 0.0000748 AC XY: 9AN XY: 120248
GnomAD4 exome AF: 0.0000560 AC: 81AN: 1446654Hom.: 0 Cov.: 34 AF XY: 0.0000654 AC XY: 47AN XY: 718930
GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152362Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15AN XY: 74506
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2020 | Reported in an individual with myopathic change with autophagy, who harbored a second PLEC variant in unknown phase (Dai et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25987458) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 21, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | PLEC: PM2 - |
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 | Oct 03, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1086 of the PLEC protein (p.Ala1086Val). This variant is present in population databases (rs529986115, gnomAD 0.08%). This missense change has been observed in individual(s) with PLEC-related disease (PMID: 25987458). ClinVar contains an entry for this variant (Variation ID: 471570). 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. 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