rs11777402

Variant names:

• chr8-143921568-G-A
• rs11777402
• NM_201384.3:c.8253C>T

Variant summary

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

The NM_201384.3(PLEC):​c.8253C>T​(p.Asn2751Asn) 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 1,612,104 control chromosomes in the GnomAD database, including 127,617 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8618 hom., cov: 33)
  • Exomes 𝑓: 0.40 (118999 hom.)
• Consequence: PLEC NM_201384.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.287
• Publications: 28 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 These names were superseded by plectin.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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 8-143921568-G-A is Benign according to our data. Variant chr8-143921568-G-A is described in ClinVar as Benign. ClinVar VariationId is 93084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.287 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEC	NM_201384.3	MANE Select	c.8253C>T	p.Asn2751Asn	synonymous	Exon 32 of 32	NP_958786.1	Q15149-4
	PLEC	NM_201378.4	MANE Plus Clinical	c.8211C>T	p.Asn2737Asn	synonymous	Exon 32 of 32	NP_958780.1	Q15149-9
	PLEC	NM_201380.4		c.8664C>T	p.Asn2888Asn	synonymous	Exon 32 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.8253C>T	p.Asn2751Asn	synonymous	Exon 32 of 32	ENSP00000344848.3	Q15149-4
	PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.8211C>T	p.Asn2737Asn	synonymous	Exon 32 of 32	ENSP00000348702.3	Q15149-9
	PLEC	ENST00000322810.8	TSL:1	c.8664C>T	p.Asn2888Asn	synonymous	Exon 32 of 32	ENSP00000323856.4	Q15149-1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45870 AN: 151970 Hom.: 8619 Cov.: 33

Gnomad AFR AF: 0.0868

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.333

GnomAD2 exomes AF: 0.345 AC: 85322 AN: 247338 AF XY: 0.356

Gnomad AFR exome AF: 0.0737

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.144

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.387

GnomAD4 exome AF: 0.397 AC: 578903 AN: 1460016 Hom.: 118999 Cov.: 84 AF XY: 0.396 AC XY: 287902 AN XY: 726252

African (AFR) AF: 0.0714 AC: 2390 AN: 33460

American (AMR) AF: 0.253 AC: 11285 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 12015 AN: 26078

East Asian (EAS) AF: 0.175 AC: 6943 AN: 39682

South Asian (SAS) AF: 0.361 AC: 31113 AN: 86186

European-Finnish (FIN) AF: 0.399 AC: 20905 AN: 52436

Middle Eastern (MID) AF: 0.402 AC: 2317 AN: 5766

European-Non Finnish (NFE) AF: 0.422 AC: 468780 AN: 1111390

Other (OTH) AF: 0.384 AC: 23155 AN: 60340

GnomAD4 genome AF: 0.301 AC: 45848 AN: 152088 Hom.: 8618 Cov.: 33 AF XY: 0.301 AC XY: 22379 AN XY: 74338

African (AFR) AF: 0.0866 AC: 3595 AN: 41522

American (AMR) AF: 0.306 AC: 4678 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 1571 AN: 3468

East Asian (EAS) AF: 0.150 AC: 775 AN: 5160

South Asian (SAS) AF: 0.351 AC: 1692 AN: 4818

European-Finnish (FIN) AF: 0.396 AC: 4189 AN: 10576

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.414 AC: 28155 AN: 67932

Other (OTH) AF: 0.330 AC: 698 AN: 2112

Alfa AF: 0.368 Hom.: 7158

Bravo AF: 0.281

Asia WGS AF: 0.221 AC: 771 AN: 3478

EpiCase AF: 0.427

EpiControl AF: 0.434

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	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	-0.89
CADD	Benign	0.014
DANN	Benign	0.84
PhyloP100		-0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	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: rs11777402; hg19: chr8-144995736; COSMIC: COSV59603428; COSMIC: COSV59603428;