rs868906137
Positions:
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_201384.3(PLEC):c.4351G>A(p.Glu1451Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000658 in 1,579,770 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00072 ( 2 hom., cov: 35)
Exomes 𝑓: 0.00065 ( 2 hom. )
Consequence
PLEC
NM_201384.3 missense
NM_201384.3 missense
Scores
1
8
10
Clinical Significance
Conservation
PhyloP100: 7.70
Genes affected
PLEC (HGNC:9069): (plectin) Plectin is a prominent member of an important family of structurally and in part functionally related proteins, termed plakins or cytolinkers, that are capable of interlinking different elements of the cytoskeleton. Plakins, with their multi-domain structure and enormous size, not only play crucial roles in maintaining cell and tissue integrity and orchestrating dynamic changes in cytoarchitecture and cell shape, but also serve as scaffolding platforms for the assembly, positioning, and regulation of signaling complexes (reviewed in PMID: 9701547, 11854008, and 17499243). Plectin is expressed as several protein isoforms in a wide range of cell types and tissues from a single gene located on chromosome 8 in humans (PMID: 8633055, 8698233). Until 2010, this locus was named plectin 1 (symbol PLEC1 in human; Plec1 in mouse and rat) and the gene product had been referred to as "hemidesmosomal protein 1" or "plectin 1, intermediate filament binding 500kDa". These names were superseded by plectin. The plectin gene locus in mouse on chromosome 15 has been analyzed in detail (PMID: 10556294, 14559777), revealing a genomic exon-intron organization with well over 40 exons spanning over 62 kb and an unusual 5' transcript complexity of plectin isoforms. Eleven exons (1-1j) have been identified that alternatively splice directly into a common exon 2 which is the first exon to encode plectin's highly conserved actin binding domain (ABD). Three additional exons (-1, 0a, and 0) splice into an alternative first coding exon (1c), and two additional exons (2alpha and 3alpha) are optionally spliced within the exons encoding the acting binding domain (exons 2-8). Analysis of the human locus has identified eight of the eleven alternative 5' exons found in mouse and rat (PMID: 14672974); exons 1i, 1j and 1h have not been confirmed in human. Furthermore, isoforms lacking the central rod domain encoded by exon 31 have been detected in mouse (PMID:10556294), rat (PMID: 9177781), and human (PMID: 11441066, 10780662, 20052759). The short alternative amino-terminal sequences encoded by the different first exons direct the targeting of the various isoforms to distinct subcellular locations (PMID: 14559777). As the expression of specific plectin isoforms was found to be dependent on cell type (tissue) and stage of development (PMID: 10556294, 12542521, 17389230) it appears that each cell type (tissue) contains a unique set (proportion and composition) of plectin isoforms, as if custom-made for specific requirements of the particular cells. Concordantly, individual isoforms were found to carry out distinct and specific functions (PMID: 14559777, 12542521, 18541706). In 1996, a number of groups reported that patients suffering from epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) lacked plectin expression in skin and muscle tissues due to defects in the plectin gene (PMID: 8698233, 8941634, 8636409, 8894687, 8696340). Two other subtypes of plectin-related EBS have been described: EBS-pyloric atresia (PA) and EBS-Ogna. For reviews of plectin-related diseases see PMID: 15810881, 19945614. Mutations in the plectin gene related to human diseases should be named based on the position in NM_000445 (variant 1, isoform 1c), unless the mutation is located within one of the other alternative first exons, in which case the position in the respective Reference Sequence should be used. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -11 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.110022515).
BP6
Variant 8-143925578-C-T is Benign according to our data. Variant chr8-143925578-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282780.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000722 (110/152300) while in subpopulation AMR AF= 0.00366 (56/15308). AF 95% confidence interval is 0.00289. There are 2 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PLEC | NM_201384.3 | c.4351G>A | p.Glu1451Lys | missense_variant | 31/32 | ENST00000345136.8 | NP_958786.1 | |
PLEC | NM_201378.4 | c.4309G>A | p.Glu1437Lys | missense_variant | 31/32 | ENST00000356346.7 | NP_958780.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLEC | ENST00000345136.8 | c.4351G>A | p.Glu1451Lys | missense_variant | 31/32 | 1 | NM_201384.3 | ENSP00000344848.3 | ||
PLEC | ENST00000356346.7 | c.4309G>A | p.Glu1437Lys | missense_variant | 31/32 | 1 | NM_201378.4 | ENSP00000348702.3 |
Frequencies
GnomAD3 genomes AF: 0.000723 AC: 110AN: 152186Hom.: 2 Cov.: 35
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GnomAD3 exomes AF: 0.000608 AC: 113AN: 185844Hom.: 1 AF XY: 0.000645 AC XY: 67AN XY: 103940
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GnomAD4 exome AF: 0.000651 AC: 929AN: 1427470Hom.: 2 Cov.: 61 AF XY: 0.000637 AC XY: 452AN XY: 709172
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GnomAD4 genome AF: 0.000722 AC: 110AN: 152300Hom.: 2 Cov.: 35 AF XY: 0.000859 AC XY: 64AN XY: 74486
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | PLEC: BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 06, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 28, 2017 | - - |
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 | Labcorp Genetics (formerly Invitae), Labcorp | Dec 07, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1478 of the PLEC protein (p.Glu1478Lys). This variant is present in population databases (no rsID available, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (Invitae). ClinVar contains an entry for this variant (Variation ID: 282780). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
PLEC-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 22, 2024 | The PLEC c.4432G>A variant is predicted to result in the amino acid substitution p.Glu1478Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.11% of alleles in individuals of Latino descent in gnomAD, which is likely too common for an undocumented disease-causing variant. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Autosomal recessive limb-girdle muscular dystrophy type 2Q Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 14, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;.;.;.;T;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;.;.;.;M;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;N;N;N;N;N;N
REVEL
Benign
Sift
Benign
T;T;T;T;T;T;T;T;T
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D
Polyphen
D;D;D;D;D;D;D;D;.
Vest4
MutPred
0.24
.;.;.;.;Gain of ubiquitination at E1588 (P = 0.0198);.;.;.;.;
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at