rs193257576

Positions:

chr8-143922662-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_201384.3(PLEC):c.7267G>A(p.Ala2423Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00498 in 1,613,304 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0052 ( 26 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 0.189

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 These names were superseded by plectin.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

BP4

Computational evidence support a benign effect (MetaRNN=0.006071478).

BP6

Variant 8-143922662-C-T is Benign according to our data. Variant chr8-143922662-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196716.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}. Variant chr8-143922662-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00312 (475/152304) while in subpopulation NFE AF= 0.0057 (388/68020). AF 95% confidence interval is 0.00524. There are 0 homozygotes in gnomad4. There are 209 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEC	NM_201384.3 linkuse as main transcript	c.7267G>A	p.Ala2423Thr	missense_variant	31/32	ENST00000345136.8	NP_958786.1
PLEC	NM_201378.4 linkuse as main transcript	c.7225G>A	p.Ala2409Thr	missense_variant	31/32	ENST00000356346.7	NP_958780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8 linkuse as main transcript	c.7267G>A	p.Ala2423Thr	missense_variant	31/32	1	NM_201384.3	ENSP00000344848		Q15149-4
PLEC	ENST00000356346.7 linkuse as main transcript	c.7225G>A	p.Ala2409Thr	missense_variant	31/32	1	NM_201378.4	ENSP00000348702		Q15149-9

Frequencies

GnomAD3 genomes

AF:

0.00312

AC:

475

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00572

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00279

AC:

691

AN:

247382

Hom.:

AF XY:

0.00288

AC XY:

388

AN XY:

134666

show subpopulations

Gnomad AFR exome

AF:

0.00124

Gnomad AMR exome

AF:

0.000902

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000948

Gnomad SAS exome

AF:

0.000854

Gnomad FIN exome

AF:

0.000987

Gnomad NFE exome

AF:

0.00503

Gnomad OTH exome

AF:

0.00233

GnomAD4 exome

AF:

0.00517

AC:

7560

AN:

1461000

Hom.:

Cov.:

AF XY:

0.00498

AC XY:

3618

AN XY:

726770

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.000940

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.000847

Gnomad4 FIN exome

AF:

0.00108

Gnomad4 NFE exome

AF:

0.00636

Gnomad4 OTH exome

AF:

0.00426

GnomAD4 genome

AF:

0.00312

AC:

475

AN:

152304

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

209

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000774

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00570

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00470

Hom.:

Bravo

AF:

0.00298

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00206

AC:

ESP6500EA

AF:

0.00572

AC:

ExAC

AF:

0.00289

AC:

350

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00529

EpiControl

AF:

0.00599

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PLEC: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2020	This variant is associated with the following publications: (PMID: 32707200) -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2014	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

PLEC-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2023

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.099

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

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.87

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

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.0061

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

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.7

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.93

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

REVEL

Benign

0.094

Sift

Uncertain

0.024

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

Sift4G

Benign

0.23

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

Polyphen

0.0080

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

Vest4

0.24

MVP

0.39

ClinPred

0.0050

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.037

gMVP

0.29

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