rs11783799

chr8-143934392-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_201384.3(PLEC):c.1095T>C(p.Asp365=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,612,054 control chromosomes in the GnomAD database, including 114,126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7889 hom., cov: 34)
  • Exomes 𝑓: 0.38 (106237 hom.)
• Consequence: PLEC NM_201384.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.06

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 These names were superseded by plectin.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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 8-143934392-A-G is Benign according to our data. Variant chr8-143934392-A-G is described in ClinVar as [Benign]. Clinvar id is 129928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143934392-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201384.3	c.1095T>C	p.Asp365=	synonymous_variant	11/32	ENST00000345136.8
PLEC	NM_201378.4	c.1053T>C	p.Asp351=	synonymous_variant	11/32	ENST00000356346.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8	c.1095T>C	p.Asp365=	synonymous_variant	11/32	1	NM_201384.3
PLEC	ENST00000356346.7	c.1053T>C	p.Asp351=	synonymous_variant	11/32	1	NM_201378.4

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44895 AN: 151976 Hom.: 7889 Cov.: 34

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.330

GnomAD3 exomes AF: 0.331 AC: 81722 AN: 246878 Hom.: 14886 AF XY: 0.342 AC XY: 46007 AN XY: 134666

Gnomad AFR exome AF: 0.0948

Gnomad AMR exome AF: 0.234

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.153

Gnomad SAS exome AF: 0.343

Gnomad FIN exome AF: 0.395

Gnomad NFE exome AF: 0.393

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.375 AC: 547851 AN: 1459960 Hom.: 106237 Cov.: 53 AF XY: 0.375 AC XY: 272702 AN XY: 726308

Gnomad4 AFR exome AF: 0.0928

Gnomad4 AMR exome AF: 0.244

Gnomad4 ASJ exome AF: 0.458

Gnomad4 EAS exome AF: 0.177

Gnomad4 SAS exome AF: 0.346

Gnomad4 FIN exome AF: 0.390

Gnomad4 NFE exome AF: 0.396

Gnomad4 OTH exome AF: 0.366

GnomAD4 genome AF: 0.295 AC: 44880 AN: 152094 Hom.: 7889 Cov.: 34 AF XY: 0.296 AC XY: 21975 AN XY: 74350

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.297

Gnomad4 ASJ AF: 0.451

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.343

Gnomad4 FIN AF: 0.390

Gnomad4 NFE AF: 0.391

Gnomad4 OTH AF: 0.327

Alfa AF: 0.355 Hom.: 4468

Bravo AF: 0.276

Asia WGS AF: 0.226 AC: 789 AN: 3478

EpiCase AF: 0.403

EpiControl AF: 0.413

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

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.Asp502Asp in exon 11 of PLEC: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 38.4% (3220/8386) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs11783799). -
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	Eurofins Ntd Llc (ga)	May 21, 2014	- -

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

Invitae

Feb 01, 2024

- -

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	0.53
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs11783799; hg19: chr8-145008560; COSMIC: COSV59633583; COSMIC: COSV59633583;