rs201465091

chr8-143923964-G-Achr8-143923964-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_201384.3(PLEC):c.5965C>T(p.Arg1989Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000445 in 1,587,282 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1989S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 2.38

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 These names were superseded by plectin.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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22412309).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000211 (32/151716) while in subpopulation NFE AF= 0.000442 (30/67892). AF 95% confidence interval is 0.000317. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. 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.5965C>T	p.Arg1989Cys	missense_variant	31/32	ENST00000345136.8
PLEC	NM_201378.4	c.5923C>T	p.Arg1975Cys	missense_variant	31/32	ENST00000356346.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8	c.5965C>T	p.Arg1989Cys	missense_variant	31/32	1	NM_201384.3
PLEC	ENST00000356346.7	c.5923C>T	p.Arg1975Cys	missense_variant	31/32	1	NM_201378.4

Frequencies

GnomAD3 genomes AF: 0.000211 AC: 32 AN: 151716 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000442

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000171 AC: 36 AN: 210496 Hom.: 0 AF XY: 0.000178 AC XY: 21 AN XY: 117728

Gnomad AFR exome AF: 0.0000813

Gnomad AMR exome AF: 0.0000600

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000470 AC: 675 AN: 1435566 Hom.: 0 Cov.: 85 AF XY: 0.000458 AC XY: 327 AN XY: 714260

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.0000454

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000469

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000595

Gnomad4 OTH exome AF: 0.000168

GnomAD4 genome AF: 0.000211 AC: 32 AN: 151716 Hom.: 0 Cov.: 35 AF XY: 0.000229 AC XY: 17 AN XY: 74110

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000442

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000855 Hom.: 0

Bravo AF: 0.000230

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000500 AC: 4

ExAC AF: 0.000112 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2015	- -

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 22, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2016 of the PLEC protein (p.Arg2016Cys). This variant is present in population databases (rs201465091, gnomAD 0.04%). 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: 196735). 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. -

Epidermolysis bullosa simplex, Ogna type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Benign	0.060
Eigen_PC	Benign	0.069
FATHMM_MKL	Benign	0.63	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;D;D;D;D;.
Vest4		0.43
MVP		0.76
ClinPred		0.11	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.097
gMVP		0.40

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: rs201465091; hg19: chr8-144998132;