chr8-143924001-C-T
Position:
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_201384.3(PLEC):c.5928G>A(p.Ala1976Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 1,588,440 control chromosomes in the GnomAD database, including 125,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.30 ( 8546 hom., cov: 36)
Exomes 𝑓: 0.40 ( 116870 hom. )
Consequence
PLEC
NM_201384.3 synonymous
NM_201384.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -7.23
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 These names were superseded by plectin.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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 8-143924001-C-T is Benign according to our data. Variant chr8-143924001-C-T is described in ClinVar as [Benign]. Clinvar id is 93068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143924001-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-7.23 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PLEC | ENST00000345136.8 | c.5928G>A | p.Ala1976Ala | synonymous_variant | 31/32 | 1 | NM_201384.3 | ENSP00000344848.3 | ||
| PLEC | ENST00000356346.7 | c.5886G>A | p.Ala1962Ala | synonymous_variant | 31/32 | 1 | NM_201378.4 | ENSP00000348702.3 |
Frequencies
GnomAD3 genomes 0.301 AC: 45782AN: 151890Hom.: 8547 Cov.: 36
GnomAD3 genomes
AF:
AC:
45782
AN:
151890
Hom.:
Cov.:
36
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.339 AC: 70041AN: 206872Hom.: 12899 AF XY: 0.351 AC XY: 40519AN XY: 115482
GnomAD3 exomes
AF:
AC:
70041
AN:
206872
Hom.:
AF XY:
AC XY:
40519
AN XY:
115482
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.396 AC: 569322AN: 1436432Hom.: 116870 Cov.: 74 AF XY: 0.396 AC XY: 282945AN XY: 714126
GnomAD4 exome
AF:
AC:
569322
AN:
1436432
Hom.:
Cov.:
74
AF XY:
AC XY:
282945
AN XY:
714126
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.301 AC: 45760AN: 152008Hom.: 8546 Cov.: 36 AF XY: 0.300 AC XY: 22292AN XY: 74286
GnomAD4 genome
AF:
AC:
45760
AN:
152008
Hom.:
Cov.:
36
AF XY:
AC XY:
22292
AN XY:
74286
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
Asia WGS
AF:
AC:
768
AN:
3474
ClinVar
Significance: Benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 13, 2015 | p.Ala2113Ala in exon 31 of PLEC: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 36.7% (2901/7894) of European American chromosomes from a broad population by the NHLBI Exome Seq uencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1140522). - |
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 18, 2013 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | - | Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. - |
not provided Benign:2
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
| Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Epidermolysis bullosa simplex with nail dystrophy Benign:1
| Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Oct 25, 2021 | - - |
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 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 04, 2025 | - - |
Epidermolysis bullosa simplex 5C, with pyloric atresia Benign:1
| Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Oct 25, 2021 | - - |
Epidermolysis bullosa simplex 5B, with muscular dystrophy Benign:1
| Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Oct 25, 2021 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2Q Benign:1
| Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Oct 25, 2021 | - - |
Epidermolysis bullosa simplex, Ogna type Benign:1
| Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Oct 25, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at