8-143925331-C-T

Variant names:

• chr8-143925331-C-T
• rs201430180
• NM_201384.3:c.4598G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_201384.3(PLEC):​c.4598G>A​(p.Arg1533Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00583 in 1,555,728 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1533W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 36)
  • Exomes 𝑓: 0.0061 (32 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.17
• Publications: 4 publications found

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 These names were superseded by plectin.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]

PLEC Gene-Disease associations (from GenCC):

• epidermolysis bullosa simplex

  Inheritance: AD Classification: STRONG Submitted by: G2P
• epidermolysis bullosa simplex 5A, Ogna type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Genomics England PanelApp
• autosomal recessive limb-girdle muscular dystrophy type 2Q

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• epidermolysis bullosa simplex 5B, with muscular dystrophy

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Genomics England PanelApp
• epidermolysis bullosa simplex 5C, with pyloric atresia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• epidermolysis bullosa simplex with nail dystrophy

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• aplasia cutis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cholestasis

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071766973).
• BP6: Variant 8-143925331-C-T is Benign according to our data. Variant chr8-143925331-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00369 (560/151938) while in subpopulation NFE AF = 0.00585 (397/67882). AF 95% confidence interval is 0.00537. There are 3 homozygotes in GnomAd4. There are 268 alleles in the male GnomAd4 subpopulation. Median coverage is 36. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEC	NM_201384.3	MANE Select	c.4598G>A	p.Arg1533Gln	missense	Exon 31 of 32	NP_958786.1
	PLEC	NM_201378.4	MANE Plus Clinical	c.4556G>A	p.Arg1519Gln	missense	Exon 31 of 32	NP_958780.1
	PLEC	NM_201380.4		c.5009G>A	p.Arg1670Gln	missense	Exon 31 of 32	NP_958782.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEC	ENST00000345136.8	TSL:1 MANE Select	c.4598G>A	p.Arg1533Gln	missense	Exon 31 of 32	ENSP00000344848.3
	PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.4556G>A	p.Arg1519Gln	missense	Exon 31 of 32	ENSP00000348702.3
	PLEC	ENST00000322810.8	TSL:1	c.5009G>A	p.Arg1670Gln	missense	Exon 31 of 32	ENSP00000323856.4

Frequencies

GnomAD3 genomes AF: 0.00369 AC: 560 AN: 151830 Hom.: 3 Cov.: 36

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.00974

Gnomad NFE AF: 0.00585

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00407 AC: 639 AN: 156822 AF XY: 0.00414

Gnomad AFR exome AF: 0.000744

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.000120

Gnomad EAS exome AF: 0.000318

Gnomad FIN exome AF: 0.00149

Gnomad NFE exome AF: 0.00684

Gnomad OTH exome AF: 0.00504

GnomAD4 exome AF: 0.00607 AC: 8516 AN: 1403790 Hom.: 32 Cov.: 75 AF XY: 0.00583 AC XY: 4055 AN XY: 695268

African (AFR) AF: 0.000968 AC: 31 AN: 32036

American (AMR) AF: 0.00221 AC: 87 AN: 39278

Ashkenazi Jewish (ASJ) AF: 0.000554 AC: 14 AN: 25276

East Asian (EAS) AF: 0.000136 AC: 5 AN: 36834

South Asian (SAS) AF: 0.00417 AC: 340 AN: 81550

European-Finnish (FIN) AF: 0.00186 AC: 65 AN: 34918

Middle Eastern (MID) AF: 0.00786 AC: 36 AN: 4580

European-Non Finnish (NFE) AF: 0.00700 AC: 7638 AN: 1090958

Other (OTH) AF: 0.00514 AC: 300 AN: 58360

GnomAD4 genome AF: 0.00369 AC: 560 AN: 151938 Hom.: 3 Cov.: 36 AF XY: 0.00361 AC XY: 268 AN XY: 74264

African (AFR) AF: 0.00116 AC: 48 AN: 41460

American (AMR) AF: 0.00327 AC: 50 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5132

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4818

European-Finnish (FIN) AF: 0.00227 AC: 24 AN: 10590

Middle Eastern (MID) AF: 0.0105 AC: 3 AN: 286

European-Non Finnish (NFE) AF: 0.00585 AC: 397 AN: 67882

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00191 Hom.: 1

Bravo AF: 0.00367

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.000727 AC: 2

ESP6500EA AF: 0.00422 AC: 26

ExAC AF: 0.00311 AC: 333

Asia WGS AF: 0.00232 AC: 8 AN: 3466

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jul 23, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29334134, 29050564)

Sep 25, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PLEC: BS2

not specified Benign:2

Feb 05, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 18, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.044
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.037
Sift	Benign	0.12	T
Sift4G	Benign	0.081	T
Polyphen		0.11	B
Vest4		0.20
MVP		0.60
ClinPred		0.015	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.30
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs201430180; hg19: chr8-144999499; COSMIC: COSV59644209;