8-143924296-C-T

Position:

• chr8-143924296-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_201384.3(PLEC):​c.5633G>A​(p.Arg1878Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,594,982 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00025 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• 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 These names were superseded by plectin.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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04541868).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00025 (38/152060) while in subpopulation SAS AF= 0.00249 (12/4826). AF 95% confidence interval is 0.00143. There are 1 homozygotes in gnomad4. There are 24 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	Protein	UniProt
PLEC	NM_201384.3	c.5633G>A	p.Arg1878Gln	missense_variant	31/32	ENST00000345136.8	NP_958786.1
PLEC	NM_201378.4	c.5591G>A	p.Arg1864Gln	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.5633G>A	p.Arg1878Gln	missense_variant	31/32	1	NM_201384.3	ENSP00000344848.3
PLEC	ENST00000356346.7	c.5591G>A	p.Arg1864Gln	missense_variant	31/32	1	NM_201378.4	ENSP00000348702.3

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 151950 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000357 AC: 77 AN: 215908 Hom.: 0 AF XY: 0.000464 AC XY: 56 AN XY: 120628

Gnomad AFR exome AF: 0.000158

Gnomad AMR exome AF: 0.000386

Gnomad ASJ exome AF: 0.000952

Gnomad EAS exome AF: 0.0000584

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000145

Gnomad OTH exome AF: 0.000547

GnomAD4 exome AF: 0.000176 AC: 254 AN: 1442922 Hom.: 0 Cov.: 73 AF XY: 0.000237 AC XY: 170 AN XY: 718190

Gnomad4 AFR exome AF: 0.0000899

Gnomad4 AMR exome AF: 0.000383

Gnomad4 ASJ exome AF: 0.000846

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.0000263

Gnomad4 NFE exome AF: 0.0000631

Gnomad4 OTH exome AF: 0.000384

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152060 Hom.: 1 Cov.: 34 AF XY: 0.000323 AC XY: 24 AN XY: 74358

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000307 Hom.: 0

Bravo AF: 0.000246

ESP6500AA AF: 0.000282 AC: 1

ESP6500EA AF: 0.000265 AC: 2

ExAC AF: 0.000309 AC: 36

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 23, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 31, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 27, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2021	- -

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 20, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1905 of the PLEC protein (p.Arg1905Gln). This variant is present in population databases (rs373617951, 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: 282724). 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	0.079
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.082	.;.;.;.;T;.;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.045	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	0.76	.;.;.;.;N;.;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.98	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.045	D;D;D;D;T;D;D;D;D
Sift4G	Benign	0.32	T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;D;D;D;D;D;D;D;.
Vest4		0.38
MVP		0.81
ClinPred		0.028	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.43

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: rs373617951; hg19: chr8-144998464; COSMIC: COSV59687277;