rs200488179

chr8-143922068-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS1

The NM_201384.3(PLEC):c.7753G>C(p.Glu2585Gln) 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 1,583,908 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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 0.0012 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0021 ( 6 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.390

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 These names were superseded by plectin.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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00796324).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00117 (178/152348) while in subpopulation NFE AF= 0.00232 (158/68022). AF 95% confidence interval is 0.00203. There are 0 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201384.3 linkuse as main transcript	c.7753G>C	p.Glu2585Gln	missense_variant	32/32	ENST00000345136.8
PLEC	NM_201378.4 linkuse as main transcript	c.7711G>C	p.Glu2571Gln	missense_variant	32/32	ENST00000356346.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8 linkuse as main transcript	c.7753G>C	p.Glu2585Gln	missense_variant	32/32	1	NM_201384.3		Q15149-4
PLEC	ENST00000356346.7 linkuse as main transcript	c.7711G>C	p.Glu2571Gln	missense_variant	32/32	1	NM_201378.4		Q15149-9

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

179

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00234

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000934

AC:

184

AN:

196898

Hom.:

AF XY:

0.000938

AC XY:

103

AN XY:

109772

show subpopulations

Gnomad AFR exome

AF:

0.0000905

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000111

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000429

Gnomad NFE exome

AF:

0.00198

Gnomad OTH exome

AF:

0.000988

GnomAD4 exome

AF:

0.00212

AC:

3038

AN:

1431560

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

1437

AN XY:

711492

show subpopulations

Gnomad4 AFR exome

AF:

0.000240

Gnomad4 AMR exome

AF:

0.0000469

Gnomad4 ASJ exome

AF:

0.000116

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000355

Gnomad4 NFE exome

AF:

0.00256

Gnomad4 OTH exome

AF:

0.00308

GnomAD4 genome

AF:

0.00117

AC:

178

AN:

152348

Hom.:

Cov.:

AF XY:

0.000913

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00232

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00178

Hom.:

Bravo

AF:

0.00117

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00129

AC:

ExAC

AF:

0.000727

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PLEC: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2020	This variant is associated with the following publications: (PMID: 25533962) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 02, 2018	- -

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

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

Cadd

Benign

4.6

Dann

Benign

0.74

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.90

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

M_CAP

Benign

0.017

MetaRNN

Benign

0.0080

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

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.52

N;N;N;N;N;N;N;N;.;N

REVEL

Benign

0.16

Sift

Benign

0.055

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

Sift4G

Benign

0.32

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

Polyphen

0.0

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

Vest4

0.060

MVP

0.42

ClinPred

0.0063

GERP RS

-8.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.053

gMVP

0.35

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