rs62522552

chr8-143927099-G-Achr8-143927099-G-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.3841-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,598,542 control chromosomes in the GnomAD database, including 31,574 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2180 hom., cov: 34)
  • Exomes 𝑓: 0.19 (29394 hom.)
• Consequence: PLEC NM_201384.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.35

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 These names were superseded by plectin.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=-0.89).
• BP6: Variant 8-143927099-G-A is Benign according to our data. Variant chr8-143927099-G-A is described in ClinVar as [Benign]. Clinvar id is 256176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143927099-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201378.4	c.3799-18C>T		intron_variant		ENST00000356346.7
PLEC	NM_201384.3	c.3841-18C>T		intron_variant		ENST00000345136.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8	c.3841-18C>T		intron_variant		1	NM_201384.3
PLEC	ENST00000356346.7	c.3799-18C>T		intron_variant		1	NM_201378.4

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22205 AN: 152114 Hom.: 2181 Cov.: 34

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0818

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.156

GnomAD3 exomes AF: 0.154 AC: 37430 AN: 243142 Hom.: 3569 AF XY: 0.157 AC XY: 20785 AN XY: 132702

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.000448

Gnomad SAS exome AF: 0.0935

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.193 AC: 278665 AN: 1446310 Hom.: 29394 Cov.: 30 AF XY: 0.190 AC XY: 136505 AN XY: 720314

Gnomad4 AFR exome AF: 0.0297

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.000303

Gnomad4 SAS exome AF: 0.0966

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.216

Gnomad4 OTH exome AF: 0.178

GnomAD4 genome AF: 0.146 AC: 22204 AN: 152232 Hom.: 2180 Cov.: 34 AF XY: 0.144 AC XY: 10686 AN XY: 74408

Gnomad4 AFR AF: 0.0384

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0819

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.212

Gnomad4 OTH AF: 0.155

Alfa AF: 0.174 Hom.: 507

Bravo AF: 0.134

Asia WGS AF: 0.0380 AC: 134 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	4.8
Dann	Benign	0.53
RBP_binding_hub_radar		0.85
RBP_regulation_power_radar		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs62522552; hg19: chr8-145001267; COSMIC: COSV59709403; COSMIC: COSV59709403;