rs7002002

Variant names:

• chr8-143923759-G-A
• rs7002002
• NM_201384.3:c.6170C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201384.3(PLEC):​c.6170C>T​(p.Ala2057Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,556,772 control chromosomes in the GnomAD database, including 123,808 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2057M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.30 (8638 hom., cov: 35)
  • Exomes 𝑓: 0.40 (115170 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 2.07
• Publications: 39 publications found

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 These names were superseded by plectin.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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=4.117787E-4).
• BP6: Variant 8-143923759-G-A is Benign according to our data. Variant chr8-143923759-G-A is described in ClinVar as Benign. ClinVar VariationId is 93071.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_201384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEC	NM_201384.3	MANE Select	c.6170C>T	p.Ala2057Val	missense	Exon 31 of 32	NP_958786.1	Q15149-4
	PLEC	NM_201378.4	MANE Plus Clinical	c.6128C>T	p.Ala2043Val	missense	Exon 31 of 32	NP_958780.1	Q15149-9
	PLEC	NM_201380.4		c.6581C>T	p.Ala2194Val	missense	Exon 31 of 32	NP_958782.1	Q15149-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEC	ENST00000345136.8	TSL:1 MANE Select	c.6170C>T	p.Ala2057Val	missense	Exon 31 of 32	ENSP00000344848.3	Q15149-4
	PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.6128C>T	p.Ala2043Val	missense	Exon 31 of 32	ENSP00000348702.3	Q15149-9
	PLEC	ENST00000322810.8	TSL:1	c.6581C>T	p.Ala2194Val	missense	Exon 31 of 32	ENSP00000323856.4	Q15149-1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45961 AN: 151946 Hom.: 8640 Cov.: 35

Gnomad AFR AF: 0.0879

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.334

GnomAD2 exomes AF: 0.344 AC: 54673 AN: 158874 AF XY: 0.355

Gnomad AFR exome AF: 0.0750

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.464

Gnomad EAS exome AF: 0.146

Gnomad FIN exome AF: 0.420

Gnomad NFE exome AF: 0.423

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.398 AC: 559054 AN: 1404716 Hom.: 115170 Cov.: 72 AF XY: 0.398 AC XY: 276667 AN XY: 695820

African (AFR) AF: 0.0714 AC: 2313 AN: 32400

American (AMR) AF: 0.257 AC: 9973 AN: 38774

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 11697 AN: 25370

East Asian (EAS) AF: 0.177 AC: 6551 AN: 36944

South Asian (SAS) AF: 0.360 AC: 29348 AN: 81472

European-Finnish (FIN) AF: 0.399 AC: 13923 AN: 34894

Middle Eastern (MID) AF: 0.402 AC: 2288 AN: 5686

European-Non Finnish (NFE) AF: 0.422 AC: 460478 AN: 1090596

Other (OTH) AF: 0.384 AC: 22483 AN: 58580

GnomAD4 genome AF: 0.302 AC: 45936 AN: 152056 Hom.: 8638 Cov.: 35 AF XY: 0.302 AC XY: 22411 AN XY: 74300

African (AFR) AF: 0.0877 AC: 3640 AN: 41514

American (AMR) AF: 0.305 AC: 4663 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 1572 AN: 3468

East Asian (EAS) AF: 0.154 AC: 792 AN: 5138

South Asian (SAS) AF: 0.352 AC: 1700 AN: 4826

European-Finnish (FIN) AF: 0.396 AC: 4191 AN: 10574

Middle Eastern (MID) AF: 0.358 AC: 103 AN: 288

European-Non Finnish (NFE) AF: 0.415 AC: 28181 AN: 67934

Other (OTH) AF: 0.331 AC: 700 AN: 2112

Alfa AF: 0.382 Hom.: 15135

Bravo AF: 0.281

TwinsUK AF: 0.423 AC: 1569

ALSPAC AF: 0.425 AC: 1637

ESP6500AA AF: 0.0789 AC: 281

ESP6500EA AF: 0.350 AC: 2590

ExAC AF: 0.294 AC: 32196

Asia WGS AF: 0.220 AC: 760 AN: 3450

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2Q (1)
-	-	1	Epidermolysis bullosa simplex 5B, with muscular dystrophy (1)
-	-	1	Epidermolysis bullosa simplex 5C, with pyloric atresia (1)
-	-	1	Epidermolysis bullosa simplex with nail dystrophy (1)
-	-	1	Epidermolysis bullosa simplex, Ogna type (1)
-	-	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
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.2
DANN	Benign	0.94
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.00041	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.11
Sift	Benign	0.78	T
Sift4G	Benign	0.32	T
Polyphen		0.0010	B
Vest4		0.067
ClinPred		0.0041	T
GERP RS		1.9
Varity_R		0.014
gMVP		0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7002002; hg19: chr8-144997927; COSMIC: COSV59606174;