rs11783772

Variant names:

• chr8-143934275-A-T
• rs11783772
• NM_201384.3:c.1169+43T>A

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.1169+43T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,608,208 control chromosomes in the GnomAD database, including 113,851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7868 hom., cov: 33)
  • Exomes 𝑓: 0.38 (105983 hom.)
• Consequence: PLEC NM_201384.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.760
• Publications: 17 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 These names were superseded by plectin.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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 8-143934275-A-T is Benign according to our data. Variant chr8-143934275-A-T is described in ClinVar as Benign. ClinVar VariationId is 256170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.387 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEC	NM_201384.3	MANE Select	c.1169+43T>A		intron	N/A	NP_958786.1
	PLEC	NM_201378.4	MANE Plus Clinical	c.1127+43T>A		intron	N/A	NP_958780.1
	PLEC	NM_201380.4		c.1580+43T>A		intron	N/A	NP_958782.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEC	ENST00000345136.8	TSL:1 MANE Select	c.1169+43T>A		intron	N/A	ENSP00000344848.3
	PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.1127+43T>A		intron	N/A	ENSP00000348702.3
	PLEC	ENST00000322810.8	TSL:1	c.1580+43T>A		intron	N/A	ENSP00000323856.4

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44831 AN: 151954 Hom.: 7868 Cov.: 33

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.328

GnomAD2 exomes AF: 0.330 AC: 79983 AN: 242186 AF XY: 0.341

Gnomad AFR exome AF: 0.0937

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.460

Gnomad EAS exome AF: 0.156

Gnomad FIN exome AF: 0.394

Gnomad NFE exome AF: 0.393

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.375 AC: 546295 AN: 1456136 Hom.: 105983 Cov.: 37 AF XY: 0.375 AC XY: 272010 AN XY: 724574

African (AFR) AF: 0.0918 AC: 3072 AN: 33460

American (AMR) AF: 0.244 AC: 10908 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 11954 AN: 26114

East Asian (EAS) AF: 0.181 AC: 7193 AN: 39682

South Asian (SAS) AF: 0.346 AC: 29854 AN: 86194

European-Finnish (FIN) AF: 0.388 AC: 19208 AN: 49492

Middle Eastern (MID) AF: 0.380 AC: 2001 AN: 5268

European-Non Finnish (NFE) AF: 0.396 AC: 440039 AN: 1110994

Other (OTH) AF: 0.366 AC: 22066 AN: 60234

GnomAD4 genome AF: 0.295 AC: 44816 AN: 152072 Hom.: 7868 Cov.: 33 AF XY: 0.295 AC XY: 21931 AN XY: 74326

African (AFR) AF: 0.107 AC: 4422 AN: 41510

American (AMR) AF: 0.297 AC: 4546 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1562 AN: 3470

East Asian (EAS) AF: 0.161 AC: 829 AN: 5158

South Asian (SAS) AF: 0.343 AC: 1654 AN: 4828

European-Finnish (FIN) AF: 0.388 AC: 4108 AN: 10586

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26546 AN: 67902

Other (OTH) AF: 0.325 AC: 687 AN: 2112

Alfa AF: 0.353 Hom.: 1874

Bravo AF: 0.276

Asia WGS AF: 0.226 AC: 788 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	19
DANN	Benign	0.91
PhyloP100		0.76
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs11783772; hg19: chr8-145008443; COSMIC: COSV59633576; COSMIC: COSV59633576;