rs7002152

Positions:

chr8-143925888-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_201384.3(PLEC):c.4045-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,540,612 control chromosomes in the GnomAD database, including 122,568 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 8676 hom., cov: 35)

Exomes 𝑓: 0.40 ( 113892 hom. )

Consequence

PLEC
NM_201384.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0003312

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -2.50

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 These names were superseded by plectin.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 (BayesDel_noAF=-0.75).

BP6

Variant 8-143925888-T-C is Benign according to our data. Variant chr8-143925888-T-C is described in ClinVar as [Benign]. Clinvar id is 93049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925888-T-C is described in Lovd as [Benign]. Variant chr8-143925888-T-C is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201378.4 linkuse as main transcript	c.4003-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000356346.7
PLEC	NM_201384.3 linkuse as main transcript	c.4045-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000345136.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8 linkuse as main transcript	c.4045-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_201384.3		Q15149-4
PLEC	ENST00000356346.7 linkuse as main transcript	c.4003-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_201378.4		Q15149-9

Frequencies

GnomAD3 genomes

AF:

0.303

AC:

46101

AN:

152144

Hom.:

8677

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0892

Gnomad AMI

AF:

0.433

Gnomad AMR

AF:

0.306

Gnomad ASJ

AF:

0.453

Gnomad EAS

AF:

0.154

Gnomad SAS

AF:

0.354

Gnomad FIN

AF:

0.396

Gnomad MID

AF:

0.344

Gnomad NFE

AF:

0.415

Gnomad OTH

AF:

0.334

GnomAD3 exomes

AF:

0.336

AC:

46212

AN:

137700

Hom.:

8726

AF XY:

0.344

AC XY:

26155

AN XY:

75932

show subpopulations

Gnomad AFR exome

AF:

0.0725

Gnomad AMR exome

AF:

0.249

Gnomad ASJ exome

AF:

0.462

Gnomad EAS exome

AF:

0.139

Gnomad SAS exome

AF:

0.355

Gnomad FIN exome

AF:

0.412

Gnomad NFE exome

AF:

0.414

Gnomad OTH exome

AF:

0.384

GnomAD4 exome

AF:

0.398

AC:

552330

AN:

1388350

Hom.:

113892

Cov.:

AF XY:

0.397

AC XY:

272458

AN XY:

686016

show subpopulations

Gnomad4 AFR exome

AF:

0.0718

Gnomad4 AMR exome

AF:

0.258

Gnomad4 ASJ exome

AF:

0.460

Gnomad4 EAS exome

AF:

0.176

Gnomad4 SAS exome

AF:

0.360

Gnomad4 FIN exome

AF:

0.397

Gnomad4 NFE exome

AF:

0.422

Gnomad4 OTH exome

AF:

0.384

GnomAD4 genome

AF:

0.303

AC:

46079

AN:

152262

Hom.:

8676

Cov.:

AF XY:

0.302

AC XY:

22484

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0889

Gnomad4 AMR

AF:

0.305

Gnomad4 ASJ

AF:

0.453

Gnomad4 EAS

AF:

0.154

Gnomad4 SAS

AF:

0.353

Gnomad4 FIN

AF:

0.396

Gnomad4 NFE

AF:

0.415

Gnomad4 OTH

AF:

0.331

Alfa

AF:

0.358

Hom.:

2527

Bravo

AF:

0.282

Asia WGS

AF:

0.223

AC:

775

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.4456-4A>G in intron 30 of PLEC: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 29.8% (2142/7200) of European American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS; dbSNP rs7002152). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 18, 2013	- -

Epidermolysis bullosa simplex with nail dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Epidermolysis bullosa simplex 5C, with pyloric atresia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Epidermolysis bullosa simplex 5B, with muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy type 2Q

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Epidermolysis bullosa simplex, Ogna type

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.10

DANN

Benign

0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00033

dbscSNV1_RF

Benign

0.032

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