rs201194946

Positions:

• chr8-143930431-G-A
• chr8-143930431-G-C
• chr8-143930431-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_201384.3(PLEC):​c.2410C>T​(p.Arg804Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,573,544 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R804Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.73

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 These names were superseded by plectin.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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08522573).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00021 (32/152314) while in subpopulation SAS AF= 0.00269 (13/4834). AF 95% confidence interval is 0.00159. There are 1 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201384.3	c.2410C>T	p.Arg804Trp	missense_variant	20/32	ENST00000345136.8
PLEC	NM_201378.4	c.2368C>T	p.Arg790Trp	missense_variant	20/32	ENST00000356346.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8	c.2410C>T	p.Arg804Trp	missense_variant	20/32	1	NM_201384.3
PLEC	ENST00000356346.7	c.2368C>T	p.Arg790Trp	missense_variant	20/32	1	NM_201378.4

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152196 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000208 AC: 37 AN: 178256 Hom.: 0 AF XY: 0.000236 AC XY: 23 AN XY: 97648

Gnomad AFR exome AF: 0.000418

Gnomad AMR exome AF: 0.0000719

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00106

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.000420

GnomAD4 exome AF: 0.000163 AC: 232 AN: 1421230 Hom.: 1 Cov.: 36 AF XY: 0.000209 AC XY: 147 AN XY: 704134

Gnomad4 AFR exome AF: 0.000276

Gnomad4 AMR exome AF: 0.0000767

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000970

Gnomad4 OTH exome AF: 0.000170

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152314 Hom.: 1 Cov.: 34 AF XY: 0.000295 AC XY: 22 AN XY: 74478

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000854 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000197 AC: 23

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss of function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PLEC p.Arg831Trp variant was not identified in the literature but was identified in dbSNP (ID: rs201194946) and ClinVar (classified as uncertain significance by Invitae and EGL Genetics). The variant was identified in control databases in 43 of 209598 chromosomes at a frequency of 0.0002052 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 27 of 25362 chromosomes (freq: 0.001065), African in 9 of 18244 chromosomes (freq: 0.000493), Other in 2 of 5848 chromosomes (freq: 0.000342), Latino in 2 of 28652 chromosomes (freq: 0.00007) and European (non-Finnish) in 3 of 89142 chromosomes (freq: 0.000034), but was not observed in the Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Arg831 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 27, 2023	- -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 831 of the PLEC protein (p.Arg831Trp). This variant is present in population databases (rs201194946, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with PLEC-related conditions. ClinVar contains an entry for this variant (Variation ID: 487334). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLEC protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Benign	0.92
Eigen	Benign	-0.086
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.57	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.085	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D;D;D;.;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;.;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;.;D
Polyphen		1.0	D;D;D;D;D;D;D;D;.;.
Vest4		0.48
MVP		0.69
ClinPred		0.065	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.21
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs201194946; hg19: chr8-145004599;