rs55895668

chr8-143926863-T-C

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.3965A>G(p.His1322Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 1,612,168 control chromosomes in the GnomAD database, including 159,271 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. H1322C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.52 (23561 hom., cov: 35)
  • Exomes 𝑓: 0.42 (135710 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.51

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 These names were superseded by plectin.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=6.7982705E-7).
• BP6: Variant 8-143926863-T-C is Benign according to our data. Variant chr8-143926863-T-C is described in ClinVar as [Benign]. Clinvar id is 129947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143926863-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.818 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201384.3	c.3965A>G	p.His1322Arg	missense_variant	30/32	ENST00000345136.8
PLEC	NM_201378.4	c.3923A>G	p.His1308Arg	missense_variant	30/32	ENST00000356346.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8	c.3965A>G	p.His1322Arg	missense_variant	30/32	1	NM_201384.3
PLEC	ENST00000356346.7	c.3923A>G	p.His1308Arg	missense_variant	30/32	1	NM_201378.4

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78767 AN: 152056 Hom.: 23523 Cov.: 35

Gnomad AFR AF: 0.825

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.464

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.491

GnomAD3 exomes AF: 0.402 AC: 100069 AN: 248740 Hom.: 22651 AF XY: 0.400 AC XY: 54110 AN XY: 135232

Gnomad AFR exome AF: 0.835

Gnomad AMR exome AF: 0.283

Gnomad ASJ exome AF: 0.471

Gnomad EAS exome AF: 0.145

Gnomad SAS exome AF: 0.359

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.425

Gnomad OTH exome AF: 0.418

GnomAD4 exome AF: 0.422 AC: 616647 AN: 1459994 Hom.: 135710 Cov.: 36 AF XY: 0.419 AC XY: 304345 AN XY: 726398

Gnomad4 AFR exome AF: 0.842

Gnomad4 AMR exome AF: 0.298

Gnomad4 ASJ exome AF: 0.470

Gnomad4 EAS exome AF: 0.176

Gnomad4 SAS exome AF: 0.362

Gnomad4 FIN exome AF: 0.401

Gnomad4 NFE exome AF: 0.427

Gnomad4 OTH exome AF: 0.437

GnomAD4 genome AF: 0.518 AC: 78842 AN: 152174 Hom.: 23561 Cov.: 35 AF XY: 0.510 AC XY: 37954 AN XY: 74394

Gnomad4 AFR AF: 0.825

Gnomad4 AMR AF: 0.393

Gnomad4 ASJ AF: 0.464

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.355

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.422

Gnomad4 OTH AF: 0.487

Alfa AF: 0.442 Hom.: 19618

Bravo AF: 0.528

TwinsUK AF: 0.430 AC: 1596

ALSPAC AF: 0.432 AC: 1666

ESP6500AA AF: 0.823 AC: 3556

ESP6500EA AF: 0.429 AC: 3666

ExAC AF: 0.412 AC: 49898

Asia WGS AF: 0.274 AC: 955 AN: 3478

EpiCase AF: 0.435

EpiControl AF: 0.443

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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.His1459Arg in exon 30 of PLEC: This variant is not expected to have clinical s ignificance because it has been identified in 42.9% (3666/8538) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs55895668). -

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

This variant is associated with the following publications: (PMID: 27346686) -

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	0.051
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	16
Dann	Benign	0.73
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.62	T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	6.8e-7	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	3.6	N;N;N;N;N;N;N;N;.;N
REVEL	Benign	0.049
Sift	Benign	1.0	T;T;T;T;T;T;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;.;T
Polyphen		0.0	B;B;B;B;B;B;B;B;.;.
Vest4		0.20
ClinPred		0.0014	T
GERP RS		3.9
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.094
gMVP		0.28

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: rs55895668; hg19: chr8-145001031; COSMIC: COSV59612396;