rs375178454

Positions:

chr8-143931950-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_201384.3(PLEC):c.2165C>T(p.Ala722Val) variant causes a missense change. The variant allele was found at a frequency of 0.000261 in 1,606,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5O:1

Conservation

PhyloP100: 3.94

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 These names were superseded by plectin.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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12800843).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000131 (20/152220) while in subpopulation SAS AF= 0.000828 (4/4832). AF 95% confidence interval is 0.000282. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEC	NM_201384.3 linkuse as main transcript	c.2165C>T	p.Ala722Val	missense_variant	18/32	ENST00000345136.8	NP_958786.1	Q15149-4
PLEC	NM_201378.4 linkuse as main transcript	c.2123C>T	p.Ala708Val	missense_variant	18/32	ENST00000356346.7	NP_958780.1	Q15149-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8 linkuse as main transcript	c.2165C>T	p.Ala722Val	missense_variant	18/32	1	NM_201384.3	ENSP00000344848.3		Q15149-4
PLEC	ENST00000356346.7 linkuse as main transcript	c.2123C>T	p.Ala708Val	missense_variant	18/32	1	NM_201378.4	ENSP00000348702.3		Q15149-9

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000143

AC:

AN:

238434

Hom.:

AF XY:

0.000176

AC XY:

AN XY:

130398

show subpopulations

Gnomad AFR exome

AF:

0.000217

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000512

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000102

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.000274

AC:

399

AN:

1454288

Hom.:

Cov.:

AF XY:

0.000267

AC XY:

193

AN XY:

722922

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000158

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000493

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000308

Gnomad4 OTH exome

AF:

0.000100

GnomAD4 genome

AF:

0.000131

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000237

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PLEC p.Ala726Val variant was not identified in the literature but was identified in dbSNP (ID: rs375178454) and ClinVar (classified as uncertain significance by Invitae, Athena Diagnostics and EGL Genetics). The variant was identified in control databases in 37 of 269810 chromosomes at a frequency of 0.0001371 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 15 of 29324 chromosomes (freq: 0.000512), Other in 1 of 6934 chromosomes (freq: 0.000144), African in 3 of 22530 chromosomes (freq: 0.000133), Latino in 4 of 34664 chromosomes (freq: 0.000115) and European (non-Finnish) in 14 of 122834 chromosomes (freq: 0.000114), but was not observed in the Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Ala726 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2017	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 07, 2016

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 06, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 749 of the PLEC protein (p.Ala749Val). This variant is present in population databases (rs375178454, gnomAD 0.05%). 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: 448056). 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. -

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpreted as Uncertain significance and reported on 11-03-2017 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.092

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

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.13

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

MetaSVM

Uncertain

0.33

MutationAssessor

Benign

1.5

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

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.1

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

REVEL

Uncertain

0.33

Sift

Uncertain

0.0060

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

Sift4G

Uncertain

0.0090

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

Polyphen

0.0090

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

Vest4

0.36

MVP

0.73

ClinPred

0.030

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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