NM_201384.3:c.3261-13G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_201384.3(PLEC):c.3261-13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,587,154 control chromosomes in the GnomAD database, including 3,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.080 ( 1549 hom., cov: 34)

Exomes 𝑓: 0.011 ( 1472 hom. )

Consequence

PLEC
NM_201384.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.172

Publications

2 publications found

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 These names were superseded by plectin.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 Gene-Disease associations (from GenCC):

epidermolysis bullosa simplex
Inheritance: AD Classification: STRONG Submitted by: G2P
epidermolysis bullosa simplex 5A, Ogna type
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Genomics England PanelApp
autosomal recessive limb-girdle muscular dystrophy type 2Q
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
congenital myasthenic syndrome
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
epidermolysis bullosa simplex 5B, with muscular dystrophy
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Genomics England PanelApp
epidermolysis bullosa simplex 5C, with pyloric atresia
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
epidermolysis bullosa simplex with nail dystrophy
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
aplasia cutis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cholestasis
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

PLEC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 8-143928005-C-T is Benign according to our data. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in CliVar as Benign. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEC	NM_201384.3 link	c.3261-13G>A		intron_variant	Intron 25 of 31	ENST00000345136.8	NP_958786.1	Q15149-4
PLEC	NM_201378.4 link	c.3219-13G>A		intron_variant	Intron 25 of 31	ENST00000356346.7	NP_958780.1	Q15149-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8 link	c.3261-13G>A		intron_variant	Intron 25 of 31	1	NM_201384.3	ENSP00000344848.3		Q15149-4
PLEC	ENST00000356346.7 link	c.3219-13G>A		intron_variant	Intron 25 of 31	1	NM_201378.4	ENSP00000348702.3		Q15149-9

Frequencies

GnomAD3 genomes

AF:

0.0794

AC:

12087

AN:

152196

Hom.:

1540

Cov.:

show subpopulations

Gnomad AFR

AF:

0.268

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0311

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00492

Gnomad OTH

AF:

0.0664

GnomAD2 exomes

AF:

0.0216

AC:

4995

AN:

231086

AF XY:

0.0169

show subpopulations

Gnomad AFR exome

AF:

0.278

Gnomad AMR exome

AF:

0.0142

Gnomad ASJ exome

AF:

0.00111

Gnomad EAS exome

AF:

0.000170

Gnomad FIN exome

AF:

0.00224

Gnomad NFE exome

AF:

0.00489

Gnomad OTH exome

AF:

0.0105

GnomAD4 exome

AF:

0.0111

AC:

15910

AN:

1434840

Hom.:

1472

Cov.:

AF XY:

0.00982

AC XY:

6967

AN XY:

709488

show subpopulations

African (AFR)

AF:

0.285

AC:

9343

AN:

32832

American (AMR)

AF:

0.0156

AC:

679

AN:

43618

Ashkenazi Jewish (ASJ)

AF:

0.00110

AC:

AN:

25350

East Asian (EAS)

AF:

0.000179

AC:

AN:

39082

South Asian (SAS)

AF:

0.000446

AC:

AN:

85164

European-Finnish (FIN)

AF:

0.00231

AC:

114

AN:

49290

Middle Eastern (MID)

AF:

0.0152

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.00412

AC:

4508

AN:

1094660

Other (OTH)

AF:

0.0187

AC:

1107

AN:

59178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

644

1288

1932

2576

3220

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

344

688

1032

1376

1720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0796

AC:

12123

AN:

152314

Hom.:

1549

Cov.:

AF XY:

0.0770

AC XY:

5736

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.268

AC:

11131

AN:

41550

American (AMR)

AF:

0.0309

AC:

473

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.000964

AC:

AN:

5188

South Asian (SAS)

AF:

0.00124

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00491

AC:

334

AN:

68028

Other (OTH)

AF:

0.0658

AC:

139

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

463

927

1390

1854

2317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0380

Hom.:

120

Bravo

AF:

0.0909

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Oct 04, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.3672-13G>A in intron 25 of PLEC: This variant is not expected to have clinical significance because it has been identified in 23.3% (896/3848) of African Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs11991798). -

May 24, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.72

(source)

DANN

Benign

0.43

PhyloP100

-0.17

RBP_binding_hub_radar

0.67

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over