rs75586449

chr8-143924346-C-T

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.5583G>A(p.Ala1861=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 1,596,840 control chromosomes in the GnomAD database, including 2,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (232 hom., cov: 34)
  • Exomes 𝑓: 0.048 (2462 hom.)
• Consequence: PLEC NM_201384.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.64

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 These names were superseded by plectin.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=-0.73).
• BP6: Variant 8-143924346-C-T is Benign according to our data. Variant chr8-143924346-C-T is described in ClinVar as [Benign]. Clinvar id is 93064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143924346-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201384.3	c.5583G>A	p.Ala1861=	synonymous_variant	31/32	ENST00000345136.8
PLEC	NM_201378.4	c.5541G>A	p.Ala1847=	synonymous_variant	31/32	ENST00000356346.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8	c.5583G>A	p.Ala1861=	synonymous_variant	31/32	1	NM_201384.3
PLEC	ENST00000356346.7	c.5541G>A	p.Ala1847=	synonymous_variant	31/32	1	NM_201378.4

Frequencies

GnomAD3 genomes AF: 0.0437 AC: 6646 AN: 152040 Hom.: 228 Cov.: 34

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0504

Gnomad EAS AF: 0.0370

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0407

Gnomad OTH AF: 0.0626

GnomAD3 exomes AF: 0.0675 AC: 14852 AN: 220062 Hom.: 801 AF XY: 0.0681 AC XY: 8366 AN XY: 122786

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.0494

Gnomad EAS exome AF: 0.0234

Gnomad SAS exome AF: 0.140

Gnomad FIN exome AF: 0.0344

Gnomad NFE exome AF: 0.0391

Gnomad OTH exome AF: 0.0646

GnomAD4 exome AF: 0.0477 AC: 68890 AN: 1444682 Hom.: 2462 Cov.: 71 AF XY: 0.0503 AC XY: 36200 AN XY: 719246

Gnomad4 AFR exome AF: 0.0120

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.0485

Gnomad4 EAS exome AF: 0.0449

Gnomad4 SAS exome AF: 0.136

Gnomad4 FIN exome AF: 0.0376

Gnomad4 NFE exome AF: 0.0381

Gnomad4 OTH exome AF: 0.0532

GnomAD4 genome AF: 0.0437 AC: 6655 AN: 152158 Hom.: 232 Cov.: 34 AF XY: 0.0465 AC XY: 3458 AN XY: 74390

Gnomad4 AFR AF: 0.0128

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.0504

Gnomad4 EAS AF: 0.0373

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.0360

Gnomad4 NFE AF: 0.0407

Gnomad4 OTH AF: 0.0620

Alfa AF: 0.0429 Hom.: 51

Bravo AF: 0.0468

Asia WGS AF: 0.0940 AC: 326 AN: 3476

EpiCase AF: 0.0423

EpiControl AF: 0.0405

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ala1998Ala 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 3.6% (272/7616) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs75586449). -
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)	Apr 22, 2013	- -

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.43
Dann	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs75586449; hg19: chr8-144998514; COSMIC: COSV59611426;