rs201041690
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_201384.3(PLEC):c.885G>A(p.Met295Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,611,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_201384.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEC | NM_201384.3 | c.885G>A | p.Met295Ile | missense_variant | 9/32 | ENST00000345136.8 | |
PLEC | NM_201378.4 | c.843G>A | p.Met281Ile | missense_variant | 9/32 | ENST00000356346.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEC | ENST00000345136.8 | c.885G>A | p.Met295Ile | missense_variant | 9/32 | 1 | NM_201384.3 | ||
PLEC | ENST00000356346.7 | c.843G>A | p.Met281Ile | missense_variant | 9/32 | 1 | NM_201378.4 |
Frequencies
GnomAD3 genomes ? AF: 0.000197 AC: 30AN: 152240Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000128 AC: 31AN: 242982Hom.: 0 AF XY: 0.0000979 AC XY: 13AN XY: 132836
GnomAD4 exome AF: 0.000210 AC: 306AN: 1459138Hom.: 0 Cov.: 35 AF XY: 0.000183 AC XY: 133AN XY: 725944
GnomAD4 genome ? AF: 0.000197 AC: 30AN: 152358Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74500
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 18, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 07, 2019 | - - |
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 01, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 322 of the PLEC protein (p.Met322Ile). This variant is present in population databases (rs201041690, gnomAD 0.02%). 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: 386477). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 13, 2022 | This alteration is classified as likely 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