rs201164522

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1629G>T(p.Glu543Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00093 in 1,612,606 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 6 hom., cov: 33)

Exomes 𝑓: 0.00054 ( 6 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.454

Publications

3 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 These names were superseded by plectin.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=0.011100531).

BP6

Variant 8-143932901-C-A is Benign according to our data. Variant chr8-143932901-C-A is described in ClinVar as Benign. ClinVar VariationId is 387324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00468 (713/152346) while in subpopulation AFR AF = 0.0159 (661/41574). AF 95% confidence interval is 0.0149. There are 6 homozygotes in GnomAd4. There are 324 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEC	NM_201384.3 link	c.1629G>T	p.Glu543Asp	missense_variant	Exon 14 of 32	ENST00000345136.8	NP_958786.1	Q15149-4
PLEC	NM_201378.4 link	c.1587G>T	p.Glu529Asp	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.1629G>T	p.Glu543Asp	missense_variant	Exon 14 of 32	1	NM_201384.3	ENSP00000344848.3		Q15149-4
PLEC	ENST00000356346.7 link	c.1587G>T	p.Glu529Asp	missense_variant	Exon 14 of 32	1	NM_201378.4	ENSP00000348702.3		Q15149-9

Frequencies

GnomAD3 genomes

AF:

0.00468

AC:

712

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00110

AC:

269

AN:

244990

AF XY:

0.000747

show subpopulations

Gnomad AFR exome

AF:

0.0160

Gnomad AMR exome

AF:

0.000640

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.000670

GnomAD4 exome

AF:

0.000539

AC:

787

AN:

1460260

Hom.:

Cov.:

AF XY:

0.000472

AC XY:

343

AN XY:

726424

show subpopulations

African (AFR)

AF:

0.0197

AC:

661

AN:

33472

American (AMR)

AF:

0.000917

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52048

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111876

Other (OTH)

AF:

0.00129

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

117

176

234

293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00468

AC:

713

AN:

152346

Hom.:

Cov.:

AF XY:

0.00435

AC XY:

324

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0159

AC:

661

AN:

41574

American (AMR)

AF:

0.00300

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

104

139

174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00174

Hom.:

Bravo

AF:

0.00554

ESP6500AA

AF:

0.0147

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00133

AC:

160

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Apr 27, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 27, 2017

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. -

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

Jan 29, 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

0.11

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.23

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

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

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

MetaRNN

Benign

0.011

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

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

1.9

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

PhyloP100

0.45

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.3

N;N;N;N;N;N;N;D;.;N;D

REVEL

Uncertain

0.34

Sift

Benign

0.095

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

Sift4G

Benign

0.19

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

Polyphen

0.41

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

Vest4

0.47

MutPred

0.36

.;.;.;.;Loss of helix (P = 0.2271);.;.;.;.;.;.;

MVP

0.71

ClinPred

0.016

GERP RS

5.1

Varity_R

0.40

gMVP

0.32

Mutation Taster

=95/5

polymorphism

(source)

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

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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