rs11993782

Positions:

• chr8-143929874-C-A
• chr8-143929874-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201384.3(PLEC):​c.2740-45G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0433 in 1,601,062 control chromosomes in the GnomAD database, including 21,165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (11089 hom., cov: 34)
  • Exomes 𝑓: 0.026 (10076 hom.)
• Consequence: PLEC NM_201384.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.401

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 These names were superseded by plectin.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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 8-143929874-C-A is Benign according to our data. Variant chr8-143929874-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 256172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEC	NM_201378.4	c.2698-45G>T		intron_variant		ENST00000356346.7	NP_958780.1
PLEC	NM_201384.3	c.2740-45G>T		intron_variant		ENST00000345136.8	NP_958786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8	c.2740-45G>T		intron_variant		1	NM_201384.3	ENSP00000344848
PLEC	ENST00000356346.7	c.2698-45G>T		intron_variant		1	NM_201378.4	ENSP00000348702

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32056 AN: 152052 Hom.: 11057 Cov.: 34

Gnomad AFR AF: 0.722

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0863

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.00697

Gnomad OTH AF: 0.156

GnomAD3 exomes AF: 0.0561 AC: 12858 AN: 229056 Hom.: 3915 AF XY: 0.0429 AC XY: 5441 AN XY: 126904

Gnomad AFR exome AF: 0.745

Gnomad AMR exome AF: 0.0397

Gnomad ASJ exome AF: 0.00870

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000996

Gnomad FIN exome AF: 0.00244

Gnomad NFE exome AF: 0.00727

Gnomad OTH exome AF: 0.0327

GnomAD4 exome AF: 0.0257 AC: 37219 AN: 1448892 Hom.: 10076 Cov.: 64 AF XY: 0.0225 AC XY: 16189 AN XY: 721110

Gnomad4 AFR exome AF: 0.755

Gnomad4 AMR exome AF: 0.0454

Gnomad4 ASJ exome AF: 0.00892

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00145

Gnomad4 FIN exome AF: 0.00245

Gnomad4 NFE exome AF: 0.00552

Gnomad4 OTH exome AF: 0.0519

GnomAD4 genome AF: 0.211 AC: 32140 AN: 152170 Hom.: 11089 Cov.: 34 AF XY: 0.204 AC XY: 15167 AN XY: 74400

Gnomad4 AFR AF: 0.722

Gnomad4 AMR AF: 0.0860

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00696

Gnomad4 OTH AF: 0.154

Alfa AF: 0.0943 Hom.: 834

Bravo AF: 0.242

Asia WGS AF: 0.0490 AC: 172 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11993782; hg19: chr8-145004042;