rs6558407

chr8-143921326-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201384.3(PLEC):c.8495G>A(p.Arg2832His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,613,640 control chromosomes in the GnomAD database, including 127,823 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2832C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.30 (8681 hom., cov: 34)
  • Exomes 𝑓: 0.40 (119142 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.31

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 These names were superseded by plectin.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=0.01626286).
• BP6: Variant 8-143921326-C-T is Benign according to our data. Variant chr8-143921326-C-T is described in ClinVar as [Benign]. Clinvar id is 93087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143921326-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201384.3	c.8495G>A	p.Arg2832His	missense_variant	32/32	ENST00000345136.8
PLEC	NM_201378.4	c.8453G>A	p.Arg2818His	missense_variant	32/32	ENST00000356346.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8	c.8495G>A	p.Arg2832His	missense_variant	32/32	1	NM_201384.3
PLEC	ENST00000356346.7	c.8453G>A	p.Arg2818His	missense_variant	32/32	1	NM_201378.4

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46082 AN: 152110 Hom.: 8682 Cov.: 34

Gnomad AFR AF: 0.0885

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.337

GnomAD3 exomes AF: 0.346 AC: 86066 AN: 248994 Hom.: 16504 AF XY: 0.357 AC XY: 48243 AN XY: 135202

Gnomad AFR exome AF: 0.0755

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.144

Gnomad SAS exome AF: 0.358

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.387

GnomAD4 exome AF: 0.397 AC: 579852 AN: 1461412 Hom.: 119142 Cov.: 145 AF XY: 0.397 AC XY: 288415 AN XY: 727056

Gnomad4 AFR exome AF: 0.0731

Gnomad4 AMR exome AF: 0.254

Gnomad4 ASJ exome AF: 0.461

Gnomad4 EAS exome AF: 0.175

Gnomad4 SAS exome AF: 0.361

Gnomad4 FIN exome AF: 0.399

Gnomad4 NFE exome AF: 0.422

Gnomad4 OTH exome AF: 0.384

GnomAD4 genome AF: 0.303 AC: 46060 AN: 152228 Hom.: 8681 Cov.: 34 AF XY: 0.302 AC XY: 22483 AN XY: 74398

Gnomad4 AFR AF: 0.0882

Gnomad4 AMR AF: 0.307

Gnomad4 ASJ AF: 0.453

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.352

Gnomad4 FIN AF: 0.397

Gnomad4 NFE AF: 0.415

Gnomad4 OTH AF: 0.334

Alfa AF: 0.391 Hom.: 3810

Bravo AF: 0.282

TwinsUK AF: 0.423 AC: 1570

ALSPAC AF: 0.425 AC: 1638

ESP6500AA AF: 0.0923 AC: 368

ESP6500EA AF: 0.412 AC: 3412

ExAC AF: 0.343 AC: 41452

EpiCase AF: 0.428

EpiControl AF: 0.435

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 18, 2013	- -
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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Arg2969His in exon 32 of PLEC: This variant is not expected to have clinical s ignificance because it has been identified in 41.2% (3412/8288) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs6558407). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Epidermolysis bullosa simplex with nail dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Epidermolysis bullosa simplex 5C, with pyloric atresia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Epidermolysis bullosa simplex 5B, with muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Epidermolysis bullosa simplex, Ogna type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	18
Dann	Benign	0.95
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.016	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.24	P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D;D;D;.;N
REVEL	Uncertain	0.33
Sift	Benign	0.030	D;D;D;D;D;D;D;D;.;D
Sift4G	Uncertain	0.060	T;T;T;T;T;T;T;T;.;T
Polyphen		0.095	B;B;B;B;B;B;B;B;.;.
Vest4		0.24
ClinPred		0.084	T
GERP RS		2.1
Varity_R		0.056
gMVP		0.63

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: rs6558407; hg19: chr8-144995494; COSMIC: COSV59633440; COSMIC: COSV59633440;