chr8-143933019-G-A

Position:

chr8-143933019-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_201384.3(PLEC):c.1511C>T(p.Ala504Val) variant causes a missense change. The variant allele was found at a frequency of 0.367 in 1,600,568 control chromosomes in the GnomAD database, including 112,871 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 7849 hom., cov: 33)

Exomes 𝑓: 0.37 ( 105022 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.63

Variant links:

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 These names were superseded by plectin.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]

PLEC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044601858).

BP6

Variant 8-143933019-G-A is Benign according to our data. Variant chr8-143933019-G-A is described in ClinVar as [Benign]. Clinvar id is 129934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143933019-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201384.3 linkuse as main transcript	c.1511C>T	p.Ala504Val	missense_variant	14/32	ENST00000345136.8
PLEC	NM_201378.4 linkuse as main transcript	c.1469C>T	p.Ala490Val	missense_variant	14/32	ENST00000356346.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8 linkuse as main transcript	c.1511C>T	p.Ala504Val	missense_variant	14/32	1	NM_201384.3		Q15149-4
PLEC	ENST00000356346.7 linkuse as main transcript	c.1469C>T	p.Ala490Val	missense_variant	14/32	1	NM_201378.4		Q15149-9

Frequencies

GnomAD3 genomes

AF:

0.295

AC:

44778

AN:

152028

Hom.:

7850

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.399

Gnomad AMR

AF:

0.297

Gnomad ASJ

AF:

0.451

Gnomad EAS

AF:

0.156

Gnomad SAS

AF:

0.343

Gnomad FIN

AF:

0.388

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.390

Gnomad OTH

AF:

0.329

GnomAD3 exomes

AF:

0.332

AC:

73811

AN:

222656

Hom.:

13236

AF XY:

0.342

AC XY:

41720

AN XY:

122044

show subpopulations

Gnomad AFR exome

AF:

0.0934

Gnomad AMR exome

AF:

0.234

Gnomad ASJ exome

AF:

0.460

Gnomad EAS exome

AF:

0.153

Gnomad SAS exome

AF:

0.343

Gnomad FIN exome

AF:

0.394

Gnomad NFE exome

AF:

0.394

Gnomad OTH exome

AF:

0.372

GnomAD4 exome

AF:

0.375

AC:

542913

AN:

1448422

Hom.:

105022

Cov.:

AF XY:

0.375

AC XY:

269836

AN XY:

719768

show subpopulations

Gnomad4 AFR exome

AF:

0.0916

Gnomad4 AMR exome

AF:

0.244

Gnomad4 ASJ exome

AF:

0.457

Gnomad4 EAS exome

AF:

0.177

Gnomad4 SAS exome

AF:

0.345

Gnomad4 FIN exome

AF:

0.389

Gnomad4 NFE exome

AF:

0.396

Gnomad4 OTH exome

AF:

0.365

GnomAD4 genome

AF:

0.294

AC:

44762

AN:

152146

Hom.:

7849

Cov.:

AF XY:

0.294

AC XY:

21904

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.106

Gnomad4 AMR

AF:

0.296

Gnomad4 ASJ

AF:

0.451

Gnomad4 EAS

AF:

0.156

Gnomad4 SAS

AF:

0.342

Gnomad4 FIN

AF:

0.388

Gnomad4 NFE

AF:

0.390

Gnomad4 OTH

AF:

0.326

Alfa

AF:

0.375

Hom.:

15924

Bravo

AF:

0.275

TwinsUK

AF:

0.399

AC:

1479

ALSPAC

AF:

0.400

AC:

1542

ESP6500AA

AF:

0.103

AC:

410

ESP6500EA

AF:

0.379

AC:

3151

ExAC

AF:

0.314

AC:

37389

Asia WGS

AF:

0.225

AC:

785

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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.Ala641Val in exon 14 of PLEC: This variant is not expected to have clinical si gnificance because it has been identified in 37.9% (3151/8312) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs11136336). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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 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

- -

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

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.068

.;.;.;.;T;.;.;.;.;.;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.34

T;T;T;T;T;T;T;T;T;T;T

MetaRNN

Benign

0.0045

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

.;.;.;.;L;.;.;.;.;.;.

MutationTaster

Benign

1.0

P;P;P;P;P;P;P;P;P

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.32

N;N;N;N;N;N;N;N;.;N;N

REVEL

Benign

0.27

Sift

Benign

0.57

T;T;T;T;T;T;T;T;.;T;T

Sift4G

Uncertain

0.013

D;D;D;D;D;D;D;D;.;D;T

Polyphen

0.0

B;B;B;B;B;B;B;B;.;.;.

Vest4

0.16

ClinPred

0.0062

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.068

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over