8-143935188-G-A

Position:

• chr8-143935188-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201384.3(PLEC):​c.718+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0497 in 1,611,628 control chromosomes in the GnomAD database, including 2,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (137 hom., cov: 33)
  • Exomes 𝑓: 0.051 (2230 hom.)
• Consequence: PLEC NM_201384.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.15

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 These names were superseded by plectin.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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 8-143935188-G-A is Benign according to our data. Variant chr8-143935188-G-A is described in ClinVar as [Benign]. Clinvar id is 93082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143935188-G-A is described in Lovd as [Likely_benign]. Variant chr8-143935188-G-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEC	NM_201384.3	c.718+10C>T		intron_variant		ENST00000345136.8	NP_958786.1
PLEC	NM_201378.4	c.676+10C>T		intron_variant		ENST00000356346.7	NP_958780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8	c.718+10C>T		intron_variant		1	NM_201384.3	ENSP00000344848.3
PLEC	ENST00000356346.7	c.676+10C>T		intron_variant		1	NM_201378.4	ENSP00000348702.3

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 5629 AN: 152156 Hom.: 137 Cov.: 33

Gnomad AFR AF: 0.00961

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0481

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.0620

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0511

Gnomad OTH AF: 0.0315

GnomAD3 exomes AF: 0.0525 AC: 13002 AN: 247490 Hom.: 513 AF XY: 0.0501 AC XY: 6752 AN XY: 134870

Gnomad AFR exome AF: 0.00863

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.0101

Gnomad SAS exome AF: 0.0380

Gnomad FIN exome AF: 0.0618

Gnomad NFE exome AF: 0.0502

Gnomad OTH exome AF: 0.0497

GnomAD4 exome AF: 0.0511 AC: 74528 AN: 1459354 Hom.: 2230 Cov.: 33 AF XY: 0.0501 AC XY: 36362 AN XY: 726120

Gnomad4 AFR exome AF: 0.00813

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.0216

Gnomad4 EAS exome AF: 0.00577

Gnomad4 SAS exome AF: 0.0392

Gnomad4 FIN exome AF: 0.0638

Gnomad4 NFE exome AF: 0.0529

Gnomad4 OTH exome AF: 0.0486

GnomAD4 genome AF: 0.0370 AC: 5629 AN: 152274 Hom.: 137 Cov.: 33 AF XY: 0.0361 AC XY: 2691 AN XY: 74444

Gnomad4 AFR AF: 0.00958

Gnomad4 AMR AF: 0.0482

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.0112

Gnomad4 SAS AF: 0.0292

Gnomad4 FIN AF: 0.0620

Gnomad4 NFE AF: 0.0511

Gnomad4 OTH AF: 0.0312

Alfa AF: 0.0463 Hom.: 96

Bravo AF: 0.0374

Asia WGS AF: 0.0210 AC: 74 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.1129+10C>T in intron 7 of PLEC: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 5.1% (438/8524) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs12545876). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 29, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.11
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12545876; hg19: chr8-145009356;