rs199720608

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_201384.3(PLEC):c.8489A>G(p.Tyr2830Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,613,818 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 11 hom., cov: 33)

Exomes 𝑓: 0.012 ( 132 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.22

Variant links:

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 These names were superseded by plectin.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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008542836).

BP6

Variant 8-143921332-T-C is Benign according to our data. Variant chr8-143921332-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 256179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143921332-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00885 (1348/152310) while in subpopulation NFE AF= 0.0128 (872/68014). AF 95% confidence interval is 0.0121. There are 11 homozygotes in gnomad4. There are 676 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEC	NM_201384.3 link	c.8489A>G	p.Tyr2830Cys	missense_variant	32/32	ENST00000345136.8	NP_958786.1	Q15149-4
PLEC	NM_201378.4 link	c.8447A>G	p.Tyr2816Cys	missense_variant	32/32	ENST00000356346.7	NP_958780.1	Q15149-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8 link	c.8489A>G	p.Tyr2830Cys	missense_variant	32/32	1	NM_201384.3	ENSP00000344848.3		Q15149-4
PLEC	ENST00000356346.7 link	c.8447A>G	p.Tyr2816Cys	missense_variant	32/32	1	NM_201378.4	ENSP00000348702.3		Q15149-9

Frequencies

GnomAD3 genomes

AF:

0.00886

AC:

1348

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00248

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.00609

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0203

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0128

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00907

AC:

2257

AN:

248974

Hom.:

AF XY:

0.00915

AC XY:

1237

AN XY:

135202

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.00255

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000981

Gnomad FIN exome

AF:

0.0209

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.00942

GnomAD4 exome

AF:

0.0123

AC:

17992

AN:

1461508

Hom.:

132

Cov.:

121

AF XY:

0.0119

AC XY:

8659

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.00200

Gnomad4 AMR exome

AF:

0.00306

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00122

Gnomad4 FIN exome

AF:

0.0190

Gnomad4 NFE exome

AF:

0.0144

Gnomad4 OTH exome

AF:

0.0101

GnomAD4 genome

AF:

0.00885

AC:

1348

AN:

152310

Hom.:

Cov.:

AF XY:

0.00908

AC XY:

676

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00248

Gnomad4 AMR

AF:

0.00608

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.0203

Gnomad4 NFE

AF:

0.0128

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00921

Hom.:

Bravo

AF:

0.00772

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00251

AC:

ESP6500EA

AF:

0.0120

AC:

ExAC

AF:

0.00949

AC:

1147

EpiCase

AF:

0.0110

EpiControl

AF:

0.0105

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PLEC: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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;C5676875:Junctional epidermolysis bullosa with pyloric atresia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 07, 2021

- -

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.19

.;.;.;.;T;.;.;.;.;.

Eigen

Benign

0.034

Eigen_PC

Benign

0.049

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.92

D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0085

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.7

.;.;.;.;M;.;.;.;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-4.6

D;D;D;D;D;D;D;D;.;D

REVEL

Uncertain

0.44

Sift

Benign

0.20

T;T;T;T;T;T;T;T;.;T

Sift4G

Benign

0.082

T;T;T;T;T;T;T;T;.;T

Polyphen

0.74

P;P;P;P;P;P;P;P;.;.

Vest4

0.36

MVP

0.56

ClinPred

0.036

GERP RS

3.8

Varity_R

0.16

gMVP

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over