rs201070741

chr8-143924276-C-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.5653G>A(p.Ala1885Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,596,422 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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. A1885V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0020 (41 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.09

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 These names were superseded by plectin.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=0.0057498217).
• BP6: Variant 8-143924276-C-T is Benign according to our data. Variant chr8-143924276-C-T is described in ClinVar as [Benign]. Clinvar id is 282287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143924276-C-T is described in Lovd as [Benign]. Variant chr8-143924276-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0026 (395/151878) while in subpopulation EAS AF= 0.0374 (191/5104). AF 95% confidence interval is 0.0331. There are 2 homozygotes in gnomad4. There are 213 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201384.3	c.5653G>A	p.Ala1885Thr	missense_variant	31/32	ENST00000345136.8
PLEC	NM_201378.4	c.5611G>A	p.Ala1871Thr	missense_variant	31/32	ENST00000356346.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8	c.5653G>A	p.Ala1885Thr	missense_variant	31/32	1	NM_201384.3
PLEC	ENST00000356346.7	c.5611G>A	p.Ala1871Thr	missense_variant	31/32	1	NM_201378.4

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 396 AN: 151768 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0373

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00927

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000604

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00437 AC: 963 AN: 220288 Hom.: 10 AF XY: 0.00389 AC XY: 478 AN XY: 122894

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.00693

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.0299

Gnomad SAS exome AF: 0.00136

Gnomad FIN exome AF: 0.00703

Gnomad NFE exome AF: 0.000666

Gnomad OTH exome AF: 0.00304

GnomAD4 exome AF: 0.00196 AC: 2838 AN: 1444544 Hom.: 41 Cov.: 73 AF XY: 0.00196 AC XY: 1412 AN XY: 719096

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.00619

Gnomad4 ASJ exome AF: 0.000422

Gnomad4 EAS exome AF: 0.0429

Gnomad4 SAS exome AF: 0.00180

Gnomad4 FIN exome AF: 0.00641

Gnomad4 NFE exome AF: 0.000259

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.00260 AC: 395 AN: 151878 Hom.: 2 Cov.: 34 AF XY: 0.00287 AC XY: 213 AN XY: 74250

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0374

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00927

Gnomad4 NFE AF: 0.000604

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000650 Hom.: 0

Bravo AF: 0.00222

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00392 AC: 464

Asia WGS AF: 0.0280 AC: 98 AN: 3468

EpiCase AF: 0.000545

EpiControl AF: 0.000357

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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 18, 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	0.083
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	0.044
Eigen_PC	Benign	-0.091
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0057	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationTaster	Benign	0.95	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.081	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;D;D;D;D;D;D;D;.
Vest4		0.55
MVP		0.76
ClinPred		0.013	T
GERP RS		4.0
Varity_R		0.059
gMVP		0.45

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: rs201070741; hg19: chr8-144998444; COSMIC: COSV59710437;