chr8-143927616-A-G

Variant names:

Variant summary

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

The NM_201380.4(PLEC):c.3961T>C(p.Leu1321Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.387 in 1,582,652 control chromosomes in the GnomAD database, including 124,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 8654 hom., cov: 35)

Exomes 𝑓: 0.40 ( 116169 hom. )

Consequence

PLEC
NM_201380.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 4.46

Publications

23 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 These names were superseded by plectin.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=-0.67).

BP6

Variant 8-143927616-A-G is Benign according to our data. Variant chr8-143927616-A-G is described in ClinVar as Benign. ClinVar VariationId is 93044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

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_201384.3	MANE Select	c.3550T>C	p.Leu1184Leu	synonymous	Exon 27 of 32	NP_958786.1
PLEC	NM_201378.4	MANE Plus Clinical	c.3508T>C	p.Leu1170Leu	synonymous	Exon 27 of 32	NP_958780.1
PLEC	NM_201380.4		c.3961T>C	p.Leu1321Leu	synonymous	Exon 27 of 32	NP_958782.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLEC	ENST00000345136.8	TSL:1 MANE Select	c.3550T>C	p.Leu1184Leu	synonymous	Exon 27 of 32	ENSP00000344848.3
PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.3508T>C	p.Leu1170Leu	synonymous	Exon 27 of 32	ENSP00000348702.3
PLEC	ENST00000322810.8	TSL:1	c.3961T>C	p.Leu1321Leu	synonymous	Exon 27 of 32	ENSP00000323856.4

Frequencies

GnomAD3 genomes

AF:

0.303

AC:

46044

AN:

152102

Hom.:

8655

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:

0.353

Gnomad FIN

AF:

0.396

Gnomad MID

AF:

0.344

Gnomad NFE

AF:

0.415

Gnomad OTH

AF:

0.335

GnomAD2 exomes

AF:

0.333

AC:

66168

AN:

198830

AF XY:

0.344

show subpopulations

Gnomad AFR exome

AF:

0.0708

Gnomad AMR exome

AF:

0.239

Gnomad ASJ exome

AF:

0.461

Gnomad EAS exome

AF:

0.139

Gnomad FIN exome

AF:

0.403

Gnomad NFE exome

AF:

0.406

Gnomad OTH exome

AF:

0.379

GnomAD4 exome

AF:

0.396

AC:

566303

AN:

1430434

Hom.:

116169

Cov.:

AF XY:

0.395

AC XY:

280873

AN XY:

710246

show subpopulations

African (AFR)

AF:

0.0723

AC:

2388

AN:

33022

American (AMR)

AF:

0.249

AC:

10701

AN:

42906

Ashkenazi Jewish (ASJ)

AF:

0.460

AC:

11824

AN:

25706

East Asian (EAS)

AF:

0.174

AC:

6711

AN:

38498

South Asian (SAS)

AF:

0.359

AC:

30273

AN:

84344

European-Finnish (FIN)

AF:

0.397

AC:

15637

AN:

39374

Middle Eastern (MID)

AF:

0.401

AC:

2278

AN:

5686

European-Non Finnish (NFE)

AF:

0.421

AC:

463781

AN:

1101590

Other (OTH)

AF:

0.383

AC:

22710

AN:

59308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

21730

43460

65190

86920

108650

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14114

28228

42342

56456

70570

<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:

0.302

AC:

46021

AN:

152218

Hom.:

8654

Cov.:

AF XY:

0.302

AC XY:

22449

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0889

AC:

3696

AN:

41552

American (AMR)

AF:

0.305

AC:

4666

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.453

AC:

1573

AN:

3472

East Asian (EAS)

AF:

0.154

AC:

794

AN:

5168

South Asian (SAS)

AF:

0.352

AC:

1700

AN:

4832

European-Finnish (FIN)

AF:

0.396

AC:

4206

AN:

10614

Middle Eastern (MID)

AF:

0.353

AC:

103

AN:

292

European-Non Finnish (NFE)

AF:

0.415

AC:

28188

AN:

67964

Other (OTH)

AF:

0.332

AC:

701

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1593

3185

4778

6370

7963

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

454

908

1362

1816

2270

<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:

0.368

Hom.:

4695

Bravo

AF:

0.282

Asia WGS

AF:

0.221

AC:

770

AN:

3474

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

Autosomal recessive limb-girdle muscular dystrophy type 2Q (1)

Epidermolysis bullosa simplex 5B, with muscular dystrophy (1)

Epidermolysis bullosa simplex 5C, with pyloric atresia (1)

Epidermolysis bullosa simplex with nail dystrophy (1)

Epidermolysis bullosa simplex, Ogna type (1)

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

BayesDel_noAF

Benign

-0.67

CADD

Benign

6.2

(source)

DANN

Benign

0.46

PhyloP100

4.5

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

3.5

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over