rs147838690

Positions:

chr8-143924452-C-T

Variant summary

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

The NM_201384.3(PLEC):c.5477G>A(p.Arg1826Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,553,096 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1826W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.010 ( 21 hom., cov: 34)

Exomes 𝑓: 0.012 ( 153 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.00500

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 These names were superseded by plectin.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=0.0033517182).

BP6

Variant 8-143924452-C-T is Benign according to our data. Variant chr8-143924452-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143924452-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0104 (1574/151388) while in subpopulation NFE AF= 0.0118 (800/67752). AF 95% confidence interval is 0.0111. There are 21 homozygotes in gnomad4. There are 874 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEC	NM_201384.3 linkuse as main transcript	c.5477G>A	p.Arg1826Gln	missense_variant	31/32	ENST00000345136.8	NP_958786.1
PLEC	NM_201378.4 linkuse as main transcript	c.5435G>A	p.Arg1812Gln	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.5477G>A	p.Arg1826Gln	missense_variant	31/32	1	NM_201384.3	ENSP00000344848		Q15149-4
PLEC	ENST00000356346.7 linkuse as main transcript	c.5435G>A	p.Arg1812Gln	missense_variant	31/32	1	NM_201378.4	ENSP00000348702		Q15149-9

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1573

AN:

151280

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00221

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00421

Gnomad ASJ

AF:

0.000867

Gnomad EAS

AF:

0.000393

Gnomad SAS

AF:

0.00438

Gnomad FIN

AF:

0.0542

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.0101

GnomAD3 exomes

AF:

0.00930

AC:

1532

AN:

164778

Hom.:

AF XY:

0.00929

AC XY:

863

AN XY:

92880

show subpopulations

Gnomad AFR exome

AF:

0.00182

Gnomad AMR exome

AF:

0.00377

Gnomad ASJ exome

AF:

0.00141

Gnomad EAS exome

AF:

0.000383

Gnomad SAS exome

AF:

0.00335

Gnomad FIN exome

AF:

0.0513

Gnomad NFE exome

AF:

0.0121

Gnomad OTH exome

AF:

0.00944

GnomAD4 exome

AF:

0.0115

AC:

16175

AN:

1401708

Hom.:

153

Cov.:

AF XY:

0.0113

AC XY:

7827

AN XY:

694956

show subpopulations

Gnomad4 AFR exome

AF:

0.00146

Gnomad4 AMR exome

AF:

0.00364

Gnomad4 ASJ exome

AF:

0.00126

Gnomad4 EAS exome

AF:

0.0000824

Gnomad4 SAS exome

AF:

0.00424

Gnomad4 FIN exome

AF:

0.0485

Gnomad4 NFE exome

AF:

0.0122

Gnomad4 OTH exome

AF:

0.0102

GnomAD4 genome

AF:

0.0104

AC:

1574

AN:

151388

Hom.:

Cov.:

AF XY:

0.0118

AC XY:

874

AN XY:

74010

show subpopulations

Gnomad4 AFR

AF:

0.00221

Gnomad4 AMR

AF:

0.00420

Gnomad4 ASJ

AF:

0.000867

Gnomad4 EAS

AF:

0.000394

Gnomad4 SAS

AF:

0.00459

Gnomad4 FIN

AF:

0.0542

Gnomad4 NFE

AF:

0.0118

Gnomad4 OTH

AF:

0.0100

Alfa

AF:

0.00905

Hom.:

Bravo

AF:

0.00655

ESP6500AA

AF:

0.00211

AC:

ESP6500EA

AF:

0.00764

AC:

ExAC

AF:

0.00922

AC:

984

Asia WGS

AF:

0.00116

AC:

AN:

3460

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PLEC: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 14, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 30, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2013	- -

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;C5676875:Junctional epidermolysis bullosa with pyloric atresia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 02, 2021

- -

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.071

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

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.94

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

MetaRNN

Benign

0.0034

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

MetaSVM

Uncertain

-0.048

MutationAssessor

Benign

1.1

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

MutationTaster

Benign

0.97

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

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.1

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

REVEL

Benign

0.24

Sift

Benign

0.30

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

Sift4G

Benign

0.15

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

Polyphen

1.0

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

Vest4

0.29

MVP

0.69

ClinPred

0.011

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.041

gMVP

0.48

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