8-143950291-A-G

Variant names:

Variant summary

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

The NM_201380.4(PLEC):c.416T>C(p.Val139Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,570,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00088 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000098 ( 0 hom. )

Consequence

PLEC
NM_201380.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.903

Publications

0 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 These names were superseded by plectin.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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007102281).

BP6

Variant 8-143950291-A-G is Benign according to our data. Variant chr8-143950291-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 448067.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00088 (134/152204) while in subpopulation AFR AF = 0.00315 (131/41540). AF 95% confidence interval is 0.00271. There are 0 homozygotes in GnomAd4. There are 55 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_201380.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLEC	NM_201378.4	MANE Plus Clinical	c.71-11599T>C		intron	N/A	NP_958780.1
PLEC	NM_201380.4		c.416T>C	p.Val139Ala	missense	Exon 1 of 32	NP_958782.1
PLEC	NM_000445.5		c.194-11599T>C		intron	N/A	NP_000436.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLEC	ENST00000322810.8	TSL:1	c.416T>C	p.Val139Ala	missense	Exon 1 of 32	ENSP00000323856.4
PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.71-11599T>C		intron	N/A	ENSP00000348702.3
PLEC	ENST00000436759.6	TSL:1	c.194-11599T>C		intron	N/A	ENSP00000388180.2

Frequencies

GnomAD3 genomes

AF:

0.000888

AC:

135

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00319

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000159

AC:

AN:

175930

AF XY:

0.000127

show subpopulations

Gnomad AFR exome

AF:

0.00256

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000138

Gnomad OTH exome

AF:

0.000427

GnomAD4 exome

AF:

0.0000980

AC:

139

AN:

1418444

Hom.:

Cov.:

AF XY:

0.0000870

AC XY:

AN XY:

701428

show subpopulations

African (AFR)

AF:

0.00229

AC:

AN:

32686

American (AMR)

AF:

0.0000265

AC:

AN:

37666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25358

East Asian (EAS)

AF:

0.00

AC:

AN:

37564

South Asian (SAS)

AF:

0.0000370

AC:

AN:

81152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49230

Middle Eastern (MID)

AF:

0.000350

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.0000284

AC:

AN:

1090354

Other (OTH)

AF:

0.000460

AC:

AN:

58720

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000880

AC:

134

AN:

152204

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00315

AC:

131

AN:

41540

American (AMR)

AF:

0.000196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67976

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000888

Hom.:

Bravo

AF:

0.000922

ESP6500AA

AF:

0.00240

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.8

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.054

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.43

M_CAP

Benign

0.075

MetaRNN

Benign

0.0071

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

PhyloP100

-0.90

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.30

REVEL

Benign

0.11

Sift

Benign

0.17

Sift4G

Benign

0.28

Polyphen

0.0

Vest4

0.049

MVP

0.25

ClinPred

0.020

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.029

gMVP

0.48

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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