8-143925453-C-T

Variant names:

• chr8-143925453-C-T
• rs55646585
• NM_201384.3:c.4476G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_201380.4(PLEC):​c.4887G>A​(p.Ala1629Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 1,594,896 control chromosomes in the GnomAD database, including 120,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (8225 hom., cov: 35)
  • Exomes 𝑓: 0.39 (112309 hom.)
• Consequence: PLEC NM_201380.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -5.86
• Publications: 25 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 These names were superseded by plectin.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):

• 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-143925453-C-T is Benign according to our data. Variant chr8-143925453-C-T is described in ClinVar as Benign. ClinVar VariationId is 93052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.401 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEC	NM_201384.3	MANE Select	c.4476G>A	p.Ala1492Ala	synonymous	Exon 31 of 32	NP_958786.1
	PLEC	NM_201378.4	MANE Plus Clinical	c.4434G>A	p.Ala1478Ala	synonymous	Exon 31 of 32	NP_958780.1
	PLEC	NM_201380.4		c.4887G>A	p.Ala1629Ala	synonymous	Exon 31 of 32	NP_958782.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEC	ENST00000345136.8	TSL:1 MANE Select	c.4476G>A	p.Ala1492Ala	synonymous	Exon 31 of 32	ENSP00000344848.3
	PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.4434G>A	p.Ala1478Ala	synonymous	Exon 31 of 32	ENSP00000348702.3
	PLEC	ENST00000322810.8	TSL:1	c.4887G>A	p.Ala1629Ala	synonymous	Exon 31 of 32	ENSP00000323856.4

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44808 AN: 152018 Hom.: 8226 Cov.: 35

Gnomad AFR AF: 0.0875

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.330

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.324

GnomAD2 exomes AF: 0.324 AC: 70710 AN: 218130 AF XY: 0.336

Gnomad AFR exome AF: 0.0719

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.443

Gnomad EAS exome AF: 0.104

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.398

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.387 AC: 558476 AN: 1442762 Hom.: 112309 Cov.: 65 AF XY: 0.387 AC XY: 277723 AN XY: 717942

African (AFR) AF: 0.0708 AC: 2366 AN: 33414

American (AMR) AF: 0.246 AC: 10928 AN: 44372

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 11489 AN: 26016

East Asian (EAS) AF: 0.130 AC: 5159 AN: 39584

South Asian (SAS) AF: 0.358 AC: 30749 AN: 85924

European-Finnish (FIN) AF: 0.391 AC: 14820 AN: 37914

Middle Eastern (MID) AF: 0.384 AC: 2191 AN: 5710

European-Non Finnish (NFE) AF: 0.413 AC: 458413 AN: 1109702

Other (OTH) AF: 0.372 AC: 22361 AN: 60126

GnomAD4 genome AF: 0.294 AC: 44786 AN: 152134 Hom.: 8225 Cov.: 35 AF XY: 0.294 AC XY: 21851 AN XY: 74372

African (AFR) AF: 0.0872 AC: 3626 AN: 41564

American (AMR) AF: 0.300 AC: 4587 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1515 AN: 3470

East Asian (EAS) AF: 0.117 AC: 606 AN: 5184

South Asian (SAS) AF: 0.350 AC: 1688 AN: 4828

European-Finnish (FIN) AF: 0.391 AC: 4141 AN: 10584

Middle Eastern (MID) AF: 0.338 AC: 98 AN: 290

European-Non Finnish (NFE) AF: 0.405 AC: 27507 AN: 67910

Other (OTH) AF: 0.321 AC: 678 AN: 2112

Alfa AF: 0.358 Hom.: 1962

Bravo AF: 0.274

Asia WGS AF: 0.215 AC: 747 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.91
DANN	Benign	0.90
PhyloP100		-5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=89/11	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: rs55646585; hg19: chr8-144999621; COSMIC: COSV59631985;