chr8-143921315-C-T

Position:

chr8-143921315-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_201384.3(PLEC):c.8506G>A(p.Asp2836Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00203 in 1,613,938 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2836H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0021 ( 7 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: 3.95

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 These names were superseded by plectin.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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023433745).

BP6

Variant 8-143921315-C-T is Benign according to our data. Variant chr8-143921315-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196817.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}. Variant chr8-143921315-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00131 (200/152364) while in subpopulation AMR AF= 0.00222 (34/15302). AF 95% confidence interval is 0.00163. There are 0 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201384.3 linkuse as main transcript	c.8506G>A	p.Asp2836Asn	missense_variant	32/32	ENST00000345136.8
PLEC	NM_201378.4 linkuse as main transcript	c.8464G>A	p.Asp2822Asn	missense_variant	32/32	ENST00000356346.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8 linkuse as main transcript	c.8506G>A	p.Asp2836Asn	missense_variant	32/32	1	NM_201384.3		Q15149-4
PLEC	ENST00000356346.7 linkuse as main transcript	c.8464G>A	p.Asp2822Asn	missense_variant	32/32	1	NM_201378.4		Q15149-9

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

199

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000530

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00185

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00156

AC:

388

AN:

249230

Hom.:

AF XY:

0.00161

AC XY:

218

AN XY:

135302

show subpopulations

Gnomad AFR exome

AF:

0.000584

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.000334

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.00190

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00211

AC:

3080

AN:

1461574

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

1517

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.00208

Gnomad4 ASJ exome

AF:

0.000804

Gnomad4 EAS exome

AF:

0.000655

Gnomad4 SAS exome

AF:

0.00124

Gnomad4 FIN exome

AF:

0.00139

Gnomad4 NFE exome

AF:

0.00236

Gnomad4 OTH exome

AF:

0.00177

GnomAD4 genome

AF:

0.00131

AC:

200

AN:

152364

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.00185

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00167

Hom.:

Bravo

AF:

0.00150

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000747

AC:

ESP6500EA

AF:

0.00240

AC:

ExAC

AF:

0.00131

AC:

158

EpiCase

AF:

0.00185

EpiControl

AF:

0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	PLEC: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PLEC p.Asp2973Asn variant was identified in 1 of 14 proband chromosomes (frequency: 0.071) from individuals with mesial temporal lobe epilepsy (Sha_2015_PMID:25668491). The variant was also identified in dbSNP (ID: rs200814155), ClinVar (classified as a VUS by EGL Genetics, Athena Diagnostics and Invitae and as likely benign by GeneDx), Cosmic (FATHMM predicted pathogenic; score=0.93) and LOVD 3.0. The variant was identified in control databases in 438 of 280620 chromosomes (2 homozygous) at a frequency of 0.001561 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 79 of 35366 chromosomes (freq: 0.002234), European (non-Finnish) in 245 of 128510 chromosomes (freq: 0.001906), Other in 12 of 7140 chromosomes (freq: 0.001681), European (Finnish) in 34 of 25012 chromosomes (freq: 0.001359), South Asian in 37 of 30594 chromosomes (freq: 0.001209), Ashkenazi Jewish in 9 of 10352 chromosomes (freq: 0.000869), African in 16 of 24132 chromosomes (freq: 0.000663), and East Asian in 6 of 19514 chromosomes (freq: 0.000308). The p.Asp2973 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2021

The c.8587G>A (p.D2863N) alteration is located in exon 33 (coding exon 32) of the PLEC gene. This alteration results from a G to A substitution at nucleotide position 8587, causing the aspartic acid (D) at amino acid position 2863 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

PLEC-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 04, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.78

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

M_CAP

Benign

0.053

MetaRNN

Benign

0.023

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

MetaSVM

Benign

-0.48

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-3.1

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

REVEL

Uncertain

0.32

Sift

Benign

0.12

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

Sift4G

Benign

0.14

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

Polyphen

0.29

B;B;B;B;B;B;B;B;.;.

Vest4

0.29

MVP

0.63

ClinPred

0.050

GERP RS

3.2

Varity_R

0.20

gMVP

0.58

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