rs781946435

Positions:

• chr8-143924702-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_201384.3(PLEC):​c.5227G>A​(p.Ala1743Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000456 in 1,534,416 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1743A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00046 (1 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 3.83

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 These names were superseded by plectin.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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02693528).
• BP6: Variant 8-143924702-C-T is Benign according to our data. Variant chr8-143924702-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281701.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00046 (70/152048) while in subpopulation NFE AF= 0.000765 (52/67974). AF 95% confidence interval is 0.000599. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEC	NM_201384.3	c.5227G>A	p.Ala1743Thr	missense_variant	31/32	ENST00000345136.8	NP_958786.1
PLEC	NM_201378.4	c.5185G>A	p.Ala1729Thr	missense_variant	31/32	ENST00000356346.7	NP_958780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8	c.5227G>A	p.Ala1743Thr	missense_variant	31/32	1	NM_201384.3	ENSP00000344848
PLEC	ENST00000356346.7	c.5185G>A	p.Ala1729Thr	missense_variant	31/32	1	NM_201378.4	ENSP00000348702

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152048 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000489 AC: 63 AN: 128842 Hom.: 0 AF XY: 0.000468 AC XY: 33 AN XY: 70544

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000123

Gnomad ASJ exome AF: 0.00297

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000604

Gnomad OTH exome AF: 0.00175

GnomAD4 exome AF: 0.000456 AC: 630 AN: 1382368 Hom.: 1 Cov.: 68 AF XY: 0.000504 AC XY: 344 AN XY: 682188

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.000197

Gnomad4 ASJ exome AF: 0.00311

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000474

Gnomad4 OTH exome AF: 0.000553

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152048 Hom.: 0 Cov.: 35 AF XY: 0.000458 AC XY: 34 AN XY: 74252

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000765

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.000502

ExAC AF: 0.000239 AC: 18

Asia WGS AF: 0.000290 AC: 1 AN: 3460

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2019	This variant is associated with the following publications: (PMID: 31862442) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 26, 2019	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	.;.;.;.;T;.;.;.;.
Eigen	Benign	0.047
Eigen_PC	Benign	0.010
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.027	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.0	.;.;.;.;N;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.54	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.048	D;T;T;D;T;D;D;D;D
Sift4G	Benign	0.45	T;T;T;T;T;T;T;T;T
Polyphen		0.99	D;D;D;D;D;D;D;D;.
Vest4		0.34
MVP		0.76
ClinPred		0.089	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.063
gMVP		0.30

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: rs781946435; hg19: chr8-144998870;