rs35723243

chr8-143921771-G-Achr8-143921771-G-Cchr8-143921771-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_201384.3(PLEC):c.8050C>T(p.Arg2684Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 1,611,770 control chromosomes in the GnomAD database, including 897 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2684Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (47 hom., cov: 34)
  • Exomes 𝑓: 0.031 (850 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.60

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 These names were superseded by plectin.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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035339892).
• BP6: Variant 8-143921771-G-A is Benign according to our data. Variant chr8-143921771-G-A is described in ClinVar as [Benign]. Clinvar id is 129958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143921771-G-A is described in Lovd as [Benign]. Variant chr8-143921771-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0212 (3232/152350) while in subpopulation NFE AF= 0.0335 (2279/68028). AF 95% confidence interval is 0.0324. There are 47 homozygotes in gnomad4. There are 1516 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201384.3	c.8050C>T	p.Arg2684Trp	missense_variant	32/32	ENST00000345136.8
PLEC	NM_201378.4	c.8008C>T	p.Arg2670Trp	missense_variant	32/32	ENST00000356346.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8	c.8050C>T	p.Arg2684Trp	missense_variant	32/32	1	NM_201384.3
PLEC	ENST00000356346.7	c.8008C>T	p.Arg2670Trp	missense_variant	32/32	1	NM_201378.4

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3234 AN: 152232 Hom.: 47 Cov.: 34

Gnomad AFR AF: 0.00502

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.0315

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0335

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0226 AC: 5459 AN: 241882 Hom.: 79 AF XY: 0.0227 AC XY: 2996 AN XY: 132198

Gnomad AFR exome AF: 0.00425

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0224

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.0317

Gnomad NFE exome AF: 0.0344

Gnomad OTH exome AF: 0.0231

GnomAD4 exome AF: 0.0312 AC: 45579 AN: 1459420 Hom.: 850 Cov.: 78 AF XY: 0.0307 AC XY: 22297 AN XY: 726074

Gnomad4 AFR exome AF: 0.00412

Gnomad4 AMR exome AF: 0.0107

Gnomad4 ASJ exome AF: 0.0235

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0114

Gnomad4 FIN exome AF: 0.0316

Gnomad4 NFE exome AF: 0.0359

Gnomad4 OTH exome AF: 0.0283

GnomAD4 genome AF: 0.0212 AC: 3232 AN: 152350 Hom.: 47 Cov.: 34 AF XY: 0.0204 AC XY: 1516 AN XY: 74496

Gnomad4 AFR AF: 0.00500

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00828

Gnomad4 FIN AF: 0.0315

Gnomad4 NFE AF: 0.0335

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0273 Hom.: 58

Bravo AF: 0.0191

TwinsUK AF: 0.0351 AC: 130

ALSPAC AF: 0.0345 AC: 133

ESP6500AA AF: 0.00647 AC: 28

ESP6500EA AF: 0.0331 AC: 282

ExAC AF: 0.0235 AC: 2839

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0321

EpiControl AF: 0.0332

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	18
Dann	Benign	0.75
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.37	N
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0035	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N;N;N;.;N
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;.;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;.;D
Polyphen		0.96	P;P;P;P;P;P;P;P;.;.
Vest4		0.31
ClinPred		0.030	T
GERP RS		1.3
Varity_R		0.045
gMVP		0.55

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: rs35723243; hg19: chr8-144995939;