rs116612406

chr8-143931621-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_201384.3(PLEC):c.2217G>A(p.Gln739=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00645 in 1,601,478 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (49 hom.)
• Consequence: PLEC NM_201384.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.00500

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 These names were superseded by plectin.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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 8-143931621-C-T is Benign according to our data. Variant chr8-143931621-C-T is described in ClinVar as [Benign]. Clinvar id is 129937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143931621-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.005 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0122 (1866/152356) while in subpopulation AFR AF= 0.0305 (1270/41576). AF 95% confidence interval is 0.0291. There are 21 homozygotes in gnomad4. There are 896 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201384.3	c.2217G>A	p.Gln739=	synonymous_variant	19/32	ENST00000345136.8
PLEC	NM_201378.4	c.2175G>A	p.Gln725=	synonymous_variant	19/32	ENST00000356346.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8	c.2217G>A	p.Gln739=	synonymous_variant	19/32	1	NM_201384.3
PLEC	ENST00000356346.7	c.2175G>A	p.Gln725=	synonymous_variant	19/32	1	NM_201378.4

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1858 AN: 152238 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00211

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00603

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00625 AC: 1404 AN: 224530 Hom.: 11 AF XY: 0.00601 AC XY: 733 AN XY: 121990

Gnomad AFR exome AF: 0.0308

Gnomad AMR exome AF: 0.00253

Gnomad ASJ exome AF: 0.00726

Gnomad EAS exome AF: 0.00173

Gnomad SAS exome AF: 0.00632

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.00570

Gnomad OTH exome AF: 0.00635

GnomAD4 exome AF: 0.00584 AC: 8462 AN: 1449122 Hom.: 49 Cov.: 34 AF XY: 0.00568 AC XY: 4086 AN XY: 719594

Gnomad4 AFR exome AF: 0.0322

Gnomad4 AMR exome AF: 0.00357

Gnomad4 ASJ exome AF: 0.00643

Gnomad4 EAS exome AF: 0.00110

Gnomad4 SAS exome AF: 0.00621

Gnomad4 FIN exome AF: 0.00222

Gnomad4 NFE exome AF: 0.00535

Gnomad4 OTH exome AF: 0.00631

GnomAD4 genome AF: 0.0122 AC: 1866 AN: 152356 Hom.: 21 Cov.: 33 AF XY: 0.0120 AC XY: 896 AN XY: 74502

Gnomad4 AFR AF: 0.0305

Gnomad4 AMR AF: 0.00542

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00603

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00855 Hom.: 5

Bravo AF: 0.0132

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Gln876Gln in exon 19 of PLEC: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 2.6% (108/4102) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs116612406). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 09, 2020	- -

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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	12
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs116612406; hg19: chr8-145005789; COSMIC: COSV59672358; COSMIC: COSV59672358;