rs542642242

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_201384.3(PLEC):c.5471C>T(p.Ala1824Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,548,614 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1824T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0010 ( 3 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 3.32

Publications

5 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 These names were superseded by plectin.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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008341253).

BP6

Variant 8-143924458-G-A is Benign according to our data. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764. Variant chr8-143924458-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 196764.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000772 (116/150166) while in subpopulation NFE AF = 0.00106 (71/67298). AF 95% confidence interval is 0.000858. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEC	NM_201384.3 link	c.5471C>T	p.Ala1824Val	missense_variant	Exon 31 of 32	ENST00000345136.8	NP_958786.1	Q15149-4
PLEC	NM_201378.4 link	c.5429C>T	p.Ala1810Val	missense_variant	Exon 31 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.5471C>T	p.Ala1824Val	missense_variant	Exon 31 of 32	1	NM_201384.3	ENSP00000344848.3		Q15149-4
PLEC	ENST00000356346.7 link	c.5429C>T	p.Ala1810Val	missense_variant	Exon 31 of 32	1	NM_201378.4	ENSP00000348702.3		Q15149-9

Frequencies

GnomAD3 genomes

AF:

0.000780

AC:

117

AN:

150058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000319

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00552

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000211

Gnomad FIN

AF:

0.000960

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00105

Gnomad OTH

AF:

0.000485

GnomAD2 exomes

AF:

0.00135

AC:

218

AN:

161322

AF XY:

0.00137

show subpopulations

Gnomad AFR exome

AF:

0.000539

Gnomad AMR exome

AF:

0.0000736

Gnomad ASJ exome

AF:

0.00814

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00132

Gnomad NFE exome

AF:

0.00165

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.00105

AC:

1468

AN:

1398448

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

745

AN XY:

692906

show subpopulations

African (AFR)

AF:

0.000196

AC:

AN:

30616

American (AMR)

AF:

0.0000517

AC:

AN:

38666

Ashkenazi Jewish (ASJ)

AF:

0.00656

AC:

161

AN:

24548

East Asian (EAS)

AF:

0.00

AC:

AN:

36220

South Asian (SAS)

AF:

0.000720

AC:

AN:

80598

European-Finnish (FIN)

AF:

0.00134

AC:

AN:

35140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5196

European-Non Finnish (NFE)

AF:

0.00104

AC:

1128

AN:

1089590

Other (OTH)

AF:

0.00114

AC:

AN:

57874

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

161

242

322

403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

152

190

<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:

0.000772

AC:

116

AN:

150166

Hom.:

Cov.:

AF XY:

0.000790

AC XY:

AN XY:

73430

show subpopulations

African (AFR)

AF:

0.000318

AC:

AN:

40900

American (AMR)

AF:

0.000132

AC:

AN:

15128

Ashkenazi Jewish (ASJ)

AF:

0.00552

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

4994

South Asian (SAS)

AF:

0.00

AC:

AN:

4732

European-Finnish (FIN)

AF:

0.000960

AC:

AN:

10414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.00106

AC:

AN:

67298

Other (OTH)

AF:

0.000480

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

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:

0.00219

Hom.:

Bravo

AF:

0.000680

ExAC

AF:

0.00109

AC:

116

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 20, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PLEC: BS2 -

not specified

Benign:2

Aug 11, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 29, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Oct 18, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5552C>T (p.A1851V) alteration is located in exon 32 (coding exon 31) of the PLEC gene. This alteration results from a C to T substitution at nucleotide position 5552, causing the alanine (A) at amino acid position 1851 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PLEC-related disorder

Benign:1

Jan 18, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Arrhythmogenic right ventricular dysplasia 1

Benign:1

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

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

Eigen

Benign

0.019

Eigen_PC

Benign

-0.049

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

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

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.0083

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

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

1.5

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

PhyloP100

3.3

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.6

N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.38

Sift

Benign

0.17

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

Sift4G

Benign

0.10

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

Polyphen

0.92

P;D;D;D;D;D;D;D;.

Vest4

0.36

MVP

0.74

ClinPred

0.036

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.12

gMVP

0.67

Mutation Taster

=99/1

polymorphism

(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