rs17062686

Positions:

• chr8-143918732-G-A
• chr8-143918732-G-C

Variant summary

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

The ENST00000345136.8(PLEC):​c.11089C>T​(p.Leu3697=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 1,612,994 control chromosomes in the GnomAD database, including 1,763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L3697L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.034 (138 hom., cov: 33)
  • Exomes 𝑓: 0.045 (1625 hom.)
• Consequence: PLEC ENST00000345136.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.380

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 These names were superseded by plectin.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=-0.91).
• BP6: Variant 8-143918732-G-A is Benign according to our data. Variant chr8-143918732-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143918732-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEC	NM_201384.3	c.11089C>T	p.Leu3697=	synonymous_variant	32/32	ENST00000345136.8	NP_958786.1
PLEC	NM_201378.4	c.11047C>T	p.Leu3683=	synonymous_variant	32/32	ENST00000356346.7	NP_958780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8	c.11089C>T	p.Leu3697=	synonymous_variant	32/32	1	NM_201384.3	ENSP00000344848
PLEC	ENST00000356346.7	c.11047C>T	p.Leu3683=	synonymous_variant	32/32	1	NM_201378.4	ENSP00000348702

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5160 AN: 152184 Hom.: 137 Cov.: 33

Gnomad AFR AF: 0.00827

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.0203

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0281

Gnomad FIN AF: 0.0456

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0533

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0333 AC: 8199 AN: 246348 Hom.: 175 AF XY: 0.0345 AC XY: 4646 AN XY: 134656

Gnomad AFR exome AF: 0.00693

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0284

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.0281

Gnomad FIN exome AF: 0.0429

Gnomad NFE exome AF: 0.0489

Gnomad OTH exome AF: 0.0340

GnomAD4 exome AF: 0.0455 AC: 66452 AN: 1460692 Hom.: 1625 Cov.: 69 AF XY: 0.0451 AC XY: 32758 AN XY: 726646

Gnomad4 AFR exome AF: 0.00726

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.0309

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0280

Gnomad4 FIN exome AF: 0.0432

Gnomad4 NFE exome AF: 0.0517

Gnomad4 OTH exome AF: 0.0409

GnomAD4 genome AF: 0.0339 AC: 5163 AN: 152302 Hom.: 138 Cov.: 33 AF XY: 0.0330 AC XY: 2458 AN XY: 74476

Gnomad4 AFR AF: 0.00825

Gnomad4 AMR AF: 0.0203

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0286

Gnomad4 FIN AF: 0.0456

Gnomad4 NFE AF: 0.0533

Gnomad4 OTH AF: 0.0302

Alfa AF: 0.0440 Hom.: 75

Bravo AF: 0.0309

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.0505

EpiControl AF: 0.0493

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Likely 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.Leu3834Leu in exon 32 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 4.9% (408/8274) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17062686). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	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	GeneDx	Feb 15, 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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 18, 2018	- -

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 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.20
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs17062686; hg19: chr8-144992900;