NM_201384.3:c.1706G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_201384.3(PLEC):c.1706G>A(p.Arg569Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,612,510 control chromosomes in the GnomAD database, including 317 homozygotes. In-silico tool predicts 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. R569W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 24 hom., cov: 33)

Exomes 𝑓: 0.018 ( 293 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.91

Publications

9 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 These names were superseded by plectin.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=0.0054878592).

BP6

Variant 8-143932824-C-T is Benign according to our data. Variant chr8-143932824-C-T is described in ClinVar as Benign. ClinVar VariationId is 129935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0142 (2163/152302) while in subpopulation NFE AF = 0.0215 (1460/68012). AF 95% confidence interval is 0.0206. There are 24 homozygotes in GnomAd4. There are 1068 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEC	NM_201384.3 link	c.1706G>A	p.Arg569Gln	missense_variant	Exon 14 of 32	ENST00000345136.8	NP_958786.1	Q15149-4
PLEC	NM_201378.4 link	c.1664G>A	p.Arg555Gln	missense_variant	Exon 14 of 32	ENST00000356346.7	NP_958780.1	Q15149-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8 link	c.1706G>A	p.Arg569Gln	missense_variant	Exon 14 of 32	1	NM_201384.3	ENSP00000344848.3		Q15149-4
PLEC	ENST00000356346.7 link	c.1664G>A	p.Arg555Gln	missense_variant	Exon 14 of 32	1	NM_201378.4	ENSP00000348702.3		Q15149-9

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2165

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00364

Gnomad AMI

AF:

0.0647

Gnomad AMR

AF:

0.00556

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00353

Gnomad FIN

AF:

0.0322

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0215

Gnomad OTH

AF:

0.00955

GnomAD2 exomes

AF:

0.0141

AC:

3412

AN:

242038

AF XY:

0.0144

show subpopulations

Gnomad AFR exome

AF:

0.00325

Gnomad AMR exome

AF:

0.00358

Gnomad ASJ exome

AF:

0.00957

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0273

Gnomad NFE exome

AF:

0.0216

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.0180

AC:

26247

AN:

1460208

Hom.:

293

Cov.:

AF XY:

0.0176

AC XY:

12817

AN XY:

726406

show subpopulations

African (AFR)

AF:

0.00266

AC:

AN:

33474

American (AMR)

AF:

0.00365

AC:

163

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00996

AC:

260

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00627

AC:

541

AN:

86240

European-Finnish (FIN)

AF:

0.0285

AC:

1481

AN:

52016

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0206

AC:

22861

AN:

1111860

Other (OTH)

AF:

0.0137

AC:

830

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1712

3425

5137

6850

8562

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

816

1632

2448

3264

4080

<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:

0.0142

AC:

2163

AN:

152302

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1068

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00363

AC:

151

AN:

41566

American (AMR)

AF:

0.00555

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.00332

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0322

AC:

342

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0215

AC:

1460

AN:

68012

Other (OTH)

AF:

0.00945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

112

224

335

447

559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0182

Hom.:

Bravo

AF:

0.0119

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0236

AC:

ESP6500AA

AF:

0.00502

AC:

ESP6500EA

AF:

0.0195

AC:

164

ExAC

AF:

0.0144

AC:

1730

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0182

EpiControl

AF:

0.0175

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Sep 29, 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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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.Arg706Gln in exon 14 of PLEC: This variant is not expected to have clinical si gnificance because it has been identified in 2.0% (164/8396) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs3135103). -

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. -

Jan 10, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

0.087

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.065

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

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0055

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

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

1.3

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

PhyloP100

2.9

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.3

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

REVEL

Uncertain

0.36

Sift

Benign

0.060

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

Sift4G

Benign

0.062

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

Polyphen

0.99

D;D;D;D;D;D;D;D;.;.;.

Vest4

0.32

ClinPred

0.0061

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.43

Mutation Taster

=98/2

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