rs782439290

chr8-143924614-G-A

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.5315C>T(p.Ala1772Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,540,844 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A1772A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 2.21

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 These names were superseded by plectin.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=0.07344133).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000359 (499/1389074) while in subpopulation NFE AF= 0.000411 (445/1081846). AF 95% confidence interval is 0.000379. There are 0 homozygotes in gnomad4_exome. There are 248 alleles in male gnomad4_exome subpopulation. Median coverage is 68. 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.5315C>T	p.Ala1772Val	missense_variant	31/32	ENST00000345136.8
PLEC	NM_201378.4	c.5273C>T	p.Ala1758Val	missense_variant	31/32	ENST00000356346.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8	c.5315C>T	p.Ala1772Val	missense_variant	31/32	1	NM_201384.3
PLEC	ENST00000356346.7	c.5273C>T	p.Ala1758Val	missense_variant	31/32	1	NM_201378.4

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 39 AN: 151770 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.000139 AC: 19 AN: 136938 Hom.: 0 AF XY: 0.000160 AC XY: 12 AN XY: 75230

Gnomad AFR exome AF: 0.000150

Gnomad AMR exome AF: 0.000199

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000913

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000176

Gnomad NFE exome AF: 0.000207

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000359 AC: 499 AN: 1389074 Hom.: 0 Cov.: 68 AF XY: 0.000361 AC XY: 248 AN XY: 686296

Gnomad4 AFR exome AF: 0.000314

Gnomad4 AMR exome AF: 0.000218

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000554

Gnomad4 SAS exome AF: 0.0000250

Gnomad4 FIN exome AF: 0.000118

Gnomad4 NFE exome AF: 0.000411

Gnomad4 OTH exome AF: 0.000482

GnomAD4 genome AF: 0.000257 AC: 39 AN: 151770 Hom.: 0 Cov.: 34 AF XY: 0.000202 AC XY: 15 AN XY: 74104

Gnomad4 AFR AF: 0.000363

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000962

Alfa AF: 0.000287 Hom.: 0

Bravo AF: 0.000249

ExAC AF: 0.0000913 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2017	The c.5396 C>T variant in the PLEC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.5396 C>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice models predict that c.5396 C>T may create a cryptic splice donor site in exon 32 that could supplant the natural splice donor site for intron 32. However, in the absence of RNA/functional studies, the actual effect of the c.5396 C>T change in this individual is unknown. If c.5396 C>T does not alter splicing, it will result in the A1799V missense change. The A1799V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across mammalian species. In silico protein prediction models are inconsistent in their predictions as to whether or not the variant is damaging to the protein structure/function. We interpret c.5396 C>T as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 29, 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;C5676875:Junctional epidermolysis bullosa with pyloric atresia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

The c.5396C>T (p.A1799V) alteration is located in exon 32 (coding exon 31) of the PLEC gene. This alteration results from a C to T substitution at nucleotide position 5396, causing the alanine (A) at amino acid position 1799 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Oct 30, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1799 of the PLEC protein (p.Ala1799Val). This variant is present in population databases (rs782439290, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (Invitae). ClinVar contains an entry for this variant (Variation ID: 196767). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	0.090
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.073	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.31	D
MutationTaster	Benign	0.80	N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.55	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.42	T;T;T;T;T;T;T;T;T
Sift4G	Uncertain	0.055	T;T;T;T;D;T;T;T;T
Polyphen		1.0	D;P;D;D;P;P;P;D;.
Vest4		0.46
MutPred		0.081		.;.;.;.;Gain of MoRF binding (P = 0.0758);.;.;.;.;
MVP		0.77
ClinPred		0.041	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.087
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs782439290; hg19: chr8-144998782;