8-143921001-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_201384.3(PLEC):c.8820C>G(p.Asp2940Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,612,998 control chromosomes in the GnomAD database, including 2,353 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2940V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.070 ( 1201 hom., cov: 33)

Exomes 𝑓: 0.010 ( 1152 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.799

Publications

7 publications found

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 These names were superseded by plectin.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 Gene-Disease associations (from GenCC):

epidermolysis bullosa simplex
Inheritance: AD Classification: STRONG Submitted by: G2P
epidermolysis bullosa simplex 5A, Ogna type
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Genomics England PanelApp
autosomal recessive limb-girdle muscular dystrophy type 2Q
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
congenital myasthenic syndrome
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
epidermolysis bullosa simplex 5B, with muscular dystrophy
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Genomics England PanelApp
epidermolysis bullosa simplex 5C, with pyloric atresia
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
epidermolysis bullosa simplex with nail dystrophy
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
aplasia cutis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cholestasis
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

PLEC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015553236).

BP6

Variant 8-143921001-G-C is Benign according to our data. Variant chr8-143921001-G-C is described in ClinVar as Benign. ClinVar VariationId is 129960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEC	NM_201384.3 link	c.8820C>G	p.Asp2940Glu	missense_variant	Exon 32 of 32	ENST00000345136.8	NP_958786.1
PLEC	NM_201378.4 link	c.8778C>G	p.Asp2926Glu	missense_variant	Exon 32 of 32	ENST00000356346.7	NP_958780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8 link	c.8820C>G	p.Asp2940Glu	missense_variant	Exon 32 of 32	1	NM_201384.3	ENSP00000344848.3
PLEC	ENST00000356346.7 link	c.8778C>G	p.Asp2926Glu	missense_variant	Exon 32 of 32	1	NM_201378.4	ENSP00000348702.3

Frequencies

GnomAD3 genomes

AF:

0.0696

AC:

10593

AN:

152160

Hom.:

1193

Cov.:

show subpopulations

Gnomad AFR

AF:

0.234

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0285

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00464

Gnomad OTH

AF:

0.0606

GnomAD2 exomes

AF:

0.0197

AC:

4904

AN:

248532

AF XY:

0.0156

show subpopulations

Gnomad AFR exome

AF:

0.244

Gnomad AMR exome

AF:

0.0138

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00216

Gnomad NFE exome

AF:

0.00481

Gnomad OTH exome

AF:

0.00959

GnomAD4 exome

AF:

0.0102

AC:

14897

AN:

1460720

Hom.:

1152

Cov.:

AF XY:

0.00905

AC XY:

6574

AN XY:

726738

show subpopulations

African (AFR)

AF:

0.251

AC:

8394

AN:

33480

American (AMR)

AF:

0.0150

AC:

672

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00107

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.000371

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00222

AC:

116

AN:

52276

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00405

AC:

4507

AN:

1112000

Other (OTH)

AF:

0.0175

AC:

1056

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

956

1912

2867

3823

4779

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

318

636

954

1272

1590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0698

AC:

10632

AN:

152278

Hom.:

1201

Cov.:

AF XY:

0.0675

AC XY:

5029

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.234

AC:

9718

AN:

41528

American (AMR)

AF:

0.0284

AC:

434

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00463

AC:

315

AN:

68034

Other (OTH)

AF:

0.0600

AC:

127

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

438

876

1313

1751

2189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0226

Hom.:

Bravo

AF:

0.0802

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.214

AC:

927

ESP6500EA

AF:

0.00457

AC:

ExAC

AF:

0.0237

AC:

2872

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.00420

EpiControl

AF:

0.00516

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asp3077Glu in exon 32 of PLEC: This variant is not expected to have clinical s ignificance because it has been identified in 21.4% (927/4330) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs58308209). -

Mar 25, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Jun 18, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.063

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

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.72

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

MetaRNN

Benign

0.0016

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

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

PhyloP100

0.80

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.0

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

REVEL

Benign

0.069

Sift

Benign

0.18

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

Sift4G

Benign

0.46

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

Polyphen

0.10

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

Vest4

0.15

MutPred

0.29

.;.;.;.;Gain of helix (P = 0.0325);.;.;.;.;.;

ClinPred

0.0056

GERP RS

2.0

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.8

Varity_R

0.033

gMVP

0.29

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over