rs782544250

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_201384.3(PLEC):c.3460C>T(p.Arg1154Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,586,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:2

Conservation

PhyloP100: 0.299

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 These names were superseded by plectin.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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18260592).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEC	NM_201384.3 link	c.3460C>T	p.Arg1154Trp	missense_variant	Exon 27 of 32	ENST00000345136.8	NP_958786.1	Q15149-4
PLEC	NM_201378.4 link	c.3418C>T	p.Arg1140Trp	missense_variant	Exon 27 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.3460C>T	p.Arg1154Trp	missense_variant	Exon 27 of 32	1	NM_201384.3	ENSP00000344848.3		Q15149-4
PLEC	ENST00000356346.7 link	c.3418C>T	p.Arg1140Trp	missense_variant	Exon 27 of 32	1	NM_201378.4	ENSP00000348702.3		Q15149-9

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000130

AC:

AN:

207122

Hom.:

AF XY:

0.000149

AC XY:

AN XY:

114026

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000156

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000236

Gnomad OTH exome

AF:

0.000191

GnomAD4 exome

AF:

0.000136

AC:

195

AN:

1434518

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

102

AN XY:

710276

show subpopulations

Gnomad4 AFR exome

AF:

0.0000305

Gnomad4 AMR exome

AF:

0.000116

Gnomad4 ASJ exome

AF:

0.0000391

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000202

Gnomad4 NFE exome

AF:

0.000162

Gnomad4 OTH exome

AF:

0.000135

GnomAD4 genome

AF:

0.000112

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000152

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Nov 24, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss of function; Has not been previously published as pathogenic or benign to our knowledge -

Dec 11, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

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

Other:2

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 12-08-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 05-29-2019 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Uncertain:1

Dec 31, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1181 of the PLEC protein (p.Arg1181Trp). This variant is present in population databases (rs782544250, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PLEC-related conditions. ClinVar contains an entry for this variant (Variation ID: 378372). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLEC protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.49

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

Eigen

Benign

0.026

Eigen_PC

Benign

-0.032

FATHMM_MKL

Benign

0.36

LIST_S2

Pathogenic

0.99

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

M_CAP

Benign

0.056

MetaRNN

Benign

0.18

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

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

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

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.5

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

REVEL

Benign

0.095

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0080

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

Polyphen

1.0

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

Vest4

0.49

MutPred

0.42

.;.;.;.;Gain of catalytic residue at R1291 (P = 0.0077);.;.;.;.;.;

MVP

0.36

ClinPred

0.25

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.13

gMVP

0.46

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

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