dbSNP rs7016416: PLEC:p.Ala2147Ala (chr8-143923488-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_201384.3(PLEC):c.6441G>A(p.Ala2147Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,604,480 control chromosomes in the GnomAD database, including 127,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 8634 hom., cov: 34)

Exomes 𝑓: 0.40 ( 118371 hom. )

Consequence

PLEC
NM_201384.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.98

Publications

30 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 These names were superseded by plectin.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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 8-143923488-C-T is Benign according to our data. Variant chr8-143923488-C-T is described in ClinVar as Benign. ClinVar VariationId is 93073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.98 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

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.6441G>A	p.Ala2147Ala	synonymous	Exon 31 of 32	NP_958786.1	Q15149-4
PLEC	NM_201378.4	MANE Plus Clinical	c.6399G>A	p.Ala2133Ala	synonymous	Exon 31 of 32	NP_958780.1	Q15149-9
PLEC	NM_201380.4		c.6852G>A	p.Ala2284Ala	synonymous	Exon 31 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.6441G>A	p.Ala2147Ala	synonymous	Exon 31 of 32	ENSP00000344848.3	Q15149-4
PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.6399G>A	p.Ala2133Ala	synonymous	Exon 31 of 32	ENSP00000348702.3	Q15149-9
PLEC	ENST00000322810.8	TSL:1	c.6852G>A	p.Ala2284Ala	synonymous	Exon 31 of 32	ENSP00000323856.4	Q15149-1

Frequencies

GnomAD3 genomes

AF:

0.303

AC:

45987

AN:

151868

Hom.:

8635

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0894

Gnomad AMI

AF:

0.432

Gnomad AMR

AF:

0.306

Gnomad ASJ

AF:

0.453

Gnomad EAS

AF:

0.153

Gnomad SAS

AF:

0.355

Gnomad FIN

AF:

0.397

Gnomad MID

AF:

0.344

Gnomad NFE

AF:

0.415

Gnomad OTH

AF:

0.333

GnomAD2 exomes

AF:

0.344

AC:

78598

AN:

228550

AF XY:

0.355

show subpopulations

Gnomad AFR exome

AF:

0.0759

Gnomad AMR exome

AF:

0.242

Gnomad ASJ exome

AF:

0.463

Gnomad EAS exome

AF:

0.146

Gnomad FIN exome

AF:

0.410

Gnomad NFE exome

AF:

0.418

Gnomad OTH exome

AF:

0.387

GnomAD4 exome

AF:

0.396

AC:

575868

AN:

1452494

Hom.:

118371

Cov.:

AF XY:

0.396

AC XY:

286481

AN XY:

722828

show subpopulations

African (AFR)

AF:

0.0729

AC:

2436

AN:

33438

American (AMR)

AF:

0.252

AC:

11235

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.461

AC:

12008

AN:

26070

East Asian (EAS)

AF:

0.176

AC:

6964

AN:

39644

South Asian (SAS)

AF:

0.361

AC:

31047

AN:

86108

European-Finnish (FIN)

AF:

0.399

AC:

18240

AN:

45660

Middle Eastern (MID)

AF:

0.401

AC:

2295

AN:

5728

European-Non Finnish (NFE)

AF:

0.422

AC:

468556

AN:

1111090

Other (OTH)

AF:

0.384

AC:

23087

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

23908

47816

71725

95633

119541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14158

28316

42474

56632

70790

<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:

45965

AN:

151986

Hom.:

8634

Cov.:

AF XY:

0.302

AC XY:

22426

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.0891

AC:

3694

AN:

41460

American (AMR)

AF:

0.305

AC:

4661

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.453

AC:

1573

AN:

3470

East Asian (EAS)

AF:

0.152

AC:

787

AN:

5164

South Asian (SAS)

AF:

0.353

AC:

1700

AN:

4810

European-Finnish (FIN)

AF:

0.397

AC:

4193

AN:

10566

Middle Eastern (MID)

AF:

0.353

AC:

103

AN:

292

European-Non Finnish (NFE)

AF:

0.415

AC:

28164

AN:

67940

Other (OTH)

AF:

0.330

AC:

696

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1583

3166

4749

6332

7915

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

452

904

1356

1808

2260

<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:

0.387

Hom.:

4477

Bravo

AF:

0.281

Asia WGS

AF:

0.223

AC:

774

AN:

3474

ClinVar

ClinVar submissions

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

-0.86

CADD

Benign

0.14

(source)

DANN

Benign

0.65

PhyloP100

-3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.2

Mutation Taster

=99/1

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

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