chr8-143917103-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_201384.3(PLEC):c.12718G>A(p.Ala4240Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000537 in 1,605,472 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A4240A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 1 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.05

Publications

6 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 These names were superseded by plectin.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):

PLEC-related muscular dystrophy-epidermolysis bullosa simplex spectrum disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
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), Genomics England PanelApp, Orphanet
autosomal recessive limb-girdle muscular dystrophy type 2Q
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
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: Genomics England PanelApp, Orphanet
epidermolysis bullosa simplex 5C, with pyloric atresia
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020151347).

BP6

Variant 8-143917103-C-T is Benign according to our data. Variant chr8-143917103-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 283767.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000394 (60/152292) while in subpopulation NFE AF = 0.000662 (45/68014). AF 95% confidence interval is 0.000508. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLEC	NM_201384.3	MANE Select	c.12718G>A	p.Ala4240Thr	missense	Exon 32 of 32	NP_958786.1	Q15149-4
PLEC	NM_201378.4	MANE Plus Clinical	c.12676G>A	p.Ala4226Thr	missense	Exon 32 of 32	NP_958780.1	Q15149-9
PLEC	NM_201380.4		c.13129G>A	p.Ala4377Thr	missense	Exon 32 of 32	NP_958782.1	Q15149-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLEC	ENST00000345136.8	TSL:1 MANE Select	c.12718G>A	p.Ala4240Thr	missense	Exon 32 of 32	ENSP00000344848.3	Q15149-4
PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.12676G>A	p.Ala4226Thr	missense	Exon 32 of 32	ENSP00000348702.3	Q15149-9
PLEC	ENST00000322810.8	TSL:1	c.13129G>A	p.Ala4377Thr	missense	Exon 32 of 32	ENSP00000323856.4	Q15149-1

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000662

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000279

AC:

AN:

247184

AF XY:

0.000320

show subpopulations

Gnomad AFR exome

AF:

0.0000651

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.000449

Gnomad OTH exome

AF:

0.000498

GnomAD4 exome

AF:

0.000552

AC:

802

AN:

1453180

Hom.:

Cov.:

AF XY:

0.000515

AC XY:

371

AN XY:

721014

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33334

American (AMR)

AF:

0.000269

AC:

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26034

East Asian (EAS)

AF:

0.0000507

AC:

AN:

39426

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86156

European-Finnish (FIN)

AF:

0.000210

AC:

AN:

52390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000637

AC:

704

AN:

1105522

Other (OTH)

AF:

0.00108

AC:

AN:

59956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

107

161

214

268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.000394

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41560

American (AMR)

AF:

0.000327

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000662

AC:

AN:

68014

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000421

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000710

AC:

ExAC

AF:

0.000297

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000818

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

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 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.067

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.037

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.14

PhyloP100

2.0

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.90

REVEL

Benign

0.13

Sift

Benign

0.50

Sift4G

Benign

0.66

Polyphen

0.28

Vest4

0.29

MVP

0.30

ClinPred

0.020

GERP RS

3.3

Varity_R

0.040

gMVP

0.66

Mutation Taster

=85/15

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over