rs540421549
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BS1_Supporting
The NM_201384.3(PLEC):c.5878C>T(p.Arg1960Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000047 in 1,596,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000041 ( 0 hom. )
Consequence
PLEC
NM_201384.3 missense
NM_201384.3 missense
Scores
2
10
7
Clinical Significance
Conservation
PhyloP100: 0.960
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 These names were superseded by plectin.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 Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.35160118).
BS1
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000408 (59/1444352) while in subpopulation AFR AF= 0.00063 (21/33320). AF 95% confidence interval is 0.000422. There are 0 homozygotes in gnomad4_exome. There are 25 alleles in male gnomad4_exome subpopulation. Median coverage is 74. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PLEC | ENST00000345136.8 | c.5878C>T | p.Arg1960Cys | missense_variant | Exon 31 of 32 | 1 | NM_201384.3 | ENSP00000344848.3 | ||
| PLEC | ENST00000356346.7 | c.5836C>T | p.Arg1946Cys | missense_variant | Exon 31 of 32 | 1 | NM_201378.4 | ENSP00000348702.3 |
Frequencies
GnomAD3 genomes 0.000105 AC: 16AN: 151994Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000674 AC: 15AN: 222542Hom.: 0 AF XY: 0.0000567 AC XY: 7AN XY: 123460
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GnomAD4 exome AF: 0.0000408 AC: 59AN: 1444352Hom.: 0 Cov.: 74 AF XY: 0.0000348 AC XY: 25AN XY: 718982
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GnomAD4 genome 0.000105 AC: 16AN: 152112Hom.: 0 Cov.: 34 AF XY: 0.000121 AC XY: 9AN XY: 74346
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Jul 04, 2014
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Jan 06, 2022
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Inborn genetic diseases Uncertain:1
Jul 12, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.5959C>T (p.R1987C) alteration is located in exon 32 (coding exon 31) of the PLEC gene. This alteration results from a C to T substitution at nucleotide position 5959, causing the arginine (R) at amino acid position 1987 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
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
Nov 27, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1987 of the PLEC protein (p.Arg1987Cys). This variant is present in population databases (rs540421549, gnomAD 0.04%). 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: 196733). 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. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;.;.;.;T;.;.;.;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;.;.;.;L;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D
Polyphen
D;D;D;D;D;D;D;D;.
Vest4
MutPred
0.23
.;.;.;.;Loss of MoRF binding (P = 0.0031);.;.;.;.;
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