rs201070741

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_201384.3(PLEC):c.5653G>A(p.Ala1885Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,596,422 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 34)

Exomes 𝑓: 0.0020 ( 41 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.09

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 These names were superseded by plectin.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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057498217).

BP6

Variant 8-143924276-C-T is Benign according to our data. Variant chr8-143924276-C-T is described in ClinVar as [Benign]. Clinvar id is 282287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143924276-C-T is described in Lovd as [Benign]. Variant chr8-143924276-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0026 (395/151878) while in subpopulation EAS AF= 0.0374 (191/5104). AF 95% confidence interval is 0.0331. There are 2 homozygotes in gnomad4. There are 213 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEC	NM_201384.3 link	c.5653G>A	p.Ala1885Thr	missense_variant	Exon 31 of 32	ENST00000345136.8	NP_958786.1	Q15149-4
PLEC	NM_201378.4 link	c.5611G>A	p.Ala1871Thr	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.5653G>A	p.Ala1885Thr	missense_variant	Exon 31 of 32	1	NM_201384.3	ENSP00000344848.3		Q15149-4
PLEC	ENST00000356346.7 link	c.5611G>A	p.Ala1871Thr	missense_variant	Exon 31 of 32	1	NM_201378.4	ENSP00000348702.3		Q15149-9

Frequencies

GnomAD3 genomes

AF:

0.00261

AC:

396

AN:

151768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0373

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00927

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000604

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00437

AC:

963

AN:

220288

Hom.:

AF XY:

0.00389

AC XY:

478

AN XY:

122894

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.00693

Gnomad ASJ exome

AF:

0.000105

Gnomad EAS exome

AF:

0.0299

Gnomad SAS exome

AF:

0.00136

Gnomad FIN exome

AF:

0.00703

Gnomad NFE exome

AF:

0.000666

Gnomad OTH exome

AF:

0.00304

GnomAD4 exome

AF:

0.00196

AC:

2838

AN:

1444544

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

1412

AN XY:

719096

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.00619

Gnomad4 ASJ exome

AF:

0.000422

Gnomad4 EAS exome

AF:

0.0429

Gnomad4 SAS exome

AF:

0.00180

Gnomad4 FIN exome

AF:

0.00641

Gnomad4 NFE exome

AF:

0.000259

Gnomad4 OTH exome

AF:

0.00253

GnomAD4 genome

AF:

0.00260

AC:

395

AN:

151878

Hom.:

Cov.:

AF XY:

0.00287

AC XY:

213

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.0374

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00927

Gnomad4 NFE

AF:

0.000604

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000650

Hom.:

Bravo

AF:

0.00222

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.00392

AC:

464

Asia WGS

AF:

0.0280

AC:

AN:

3468

EpiCase

AF:

0.000545

EpiControl

AF:

0.000357

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Oct 27, 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. -

Dec 15, 2019

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 06, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

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

Jan 23, 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

0.083

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.099

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

Eigen

Benign

0.044

Eigen_PC

Benign

-0.091

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.96

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

MetaRNN

Benign

0.0057

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

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

1.3

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

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.1

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

REVEL

Benign

0.28

Sift

Benign

0.081

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

Sift4G

Benign

0.11

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

Polyphen

1.0

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

Vest4

0.55

MVP

0.76

ClinPred

0.013

GERP RS

4.0

Varity_R

0.059

gMVP

0.45

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