rs786205254
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The ENST00000345136.8(PLEC):c.5024_5031del(p.Arg1675GlnfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,436,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PLEC
ENST00000345136.8 frameshift
ENST00000345136.8 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.16
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 These names were superseded by plectin.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 Pathogenic. Variant got 11 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 63 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-143924897-TGCCGCGCC-T is Pathogenic according to our data. Variant chr8-143924897-TGCCGCGCC-T is described in ClinVar as [Pathogenic]. Clinvar id is 8261.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PLEC | NM_201378.4 | c.4982_4989del | p.Arg1661GlnfsTer14 | frameshift_variant | 31/32 | ENST00000356346.7 | NP_958780.1 | |
| PLEC | NM_201384.3 | c.5024_5031del | p.Arg1675GlnfsTer14 | frameshift_variant | 31/32 | ENST00000345136.8 | NP_958786.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PLEC | ENST00000345136.8 | c.5024_5031del | p.Arg1675GlnfsTer14 | frameshift_variant | 31/32 | 1 | NM_201384.3 | ENSP00000344848 | ||
| PLEC | ENST00000356346.7 | c.4982_4989del | p.Arg1661GlnfsTer14 | frameshift_variant | 31/32 | 1 | NM_201378.4 | ENSP00000348702 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
34
GnomAD4 exome AF: 0.00000139 AC: 2AN: 1436980Hom.: 0 AF XY: 0.00000140 AC XY: 1AN XY: 714388
GnomAD4 exome
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714388
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GnomAD4 genome
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Epidermolysis bullosa simplex 5B, with muscular dystrophy Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 15, 1996 | - - |
Computational scores
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Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at