8-143923961-C-T

Position:

• chr8-143923961-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BS1_Supporting

The NM_201384.3(PLEC):​c.5968G>A​(p.Val1990Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,592,722 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 2.01

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 These names were superseded by plectin.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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3806869).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000233 (335/1440482) while in subpopulation SAS AF= 0.000374 (32/85544). AF 95% confidence interval is 0.000272. There are 0 homozygotes in gnomad4_exome. There are 159 alleles in male gnomad4_exome subpopulation. Median coverage is 85. 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	Protein	UniProt
PLEC	NM_201384.3	c.5968G>A	p.Val1990Met	missense_variant	31/32	ENST00000345136.8	NP_958786.1
PLEC	NM_201378.4	c.5926G>A	p.Val1976Met	missense_variant	31/32	ENST00000356346.7	NP_958780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8	c.5968G>A	p.Val1990Met	missense_variant	31/32	1	NM_201384.3	ENSP00000344848.3
PLEC	ENST00000356346.7	c.5926G>A	p.Val1976Met	missense_variant	31/32	1	NM_201378.4	ENSP00000348702.3

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152128 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 31 AN: 211444 Hom.: 0 AF XY: 0.000152 AC XY: 18 AN XY: 118244

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000898

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000118

Gnomad SAS exome AF: 0.000444

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000127

Gnomad OTH exome AF: 0.000186

GnomAD4 exome AF: 0.000233 AC: 335 AN: 1440482 Hom.: 0 Cov.: 85 AF XY: 0.000222 AC XY: 159 AN XY: 716716

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000904

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000374

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000253

Gnomad4 OTH exome AF: 0.000267

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152240 Hom.: 0 Cov.: 35 AF XY: 0.000255 AC XY: 19 AN XY: 74452

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.000129 AC: 15

Asia WGS AF: 0.00116 AC: 4 AN: 3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2019	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2017 of the PLEC protein (p.Val2017Met). This variant is present in population databases (rs201588551, 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: 284101). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PLEC protein function. 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. -

PLEC-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2024

The PLEC c.6049G>A variant is predicted to result in the amino acid substitution p.Val2017Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.044% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal recessive limb-girdle muscular dystrophy type 2Q Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

Aug 29, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;.;.;.;T;.;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.020	D
MutationAssessor	Uncertain	2.1	.;.;.;.;M;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.89	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.014	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D;.
Vest4		0.68
MVP		0.79
ClinPred		0.13	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.083
gMVP		0.20

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: rs201588551; hg19: chr8-144998129;