rs35775257

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_201384.3(PLEC):​c.10014C>T​(p.Val3338=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00731 in 1,613,006 control chromosomes in the GnomAD database, including 795 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 432 hom., cov: 33)
Exomes 𝑓: 0.0040 ( 363 hom. )

Consequence

PLEC
NM_201384.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.460
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 These names were superseded by plectin.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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
Variant 8-143919807-G-A is Benign according to our data. Variant chr8-143919807-G-A is described in ClinVar as [Benign]. Clinvar id is 129920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143919807-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.46 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PLECNM_201384.3 linkuse as main transcriptc.10014C>T p.Val3338= synonymous_variant 32/32 ENST00000345136.8 NP_958786.1
PLECNM_201378.4 linkuse as main transcriptc.9972C>T p.Val3324= synonymous_variant 32/32 ENST00000356346.7 NP_958780.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PLECENST00000345136.8 linkuse as main transcriptc.10014C>T p.Val3338= synonymous_variant 32/321 NM_201384.3 ENSP00000344848 Q15149-4
PLECENST00000356346.7 linkuse as main transcriptc.9972C>T p.Val3324= synonymous_variant 32/321 NM_201378.4 ENSP00000348702 Q15149-9

Frequencies

GnomAD3 genomes
AF:
0.0391
AC:
5951
AN:
152236
Hom.:
430
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.136
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0150
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000827
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.000309
Gnomad OTH
AF:
0.0282
GnomAD3 exomes
AF:
0.00974
AC:
2409
AN:
247396
Hom.:
153
AF XY:
0.00755
AC XY:
1018
AN XY:
134880
show subpopulations
Gnomad AFR exome
AF:
0.140
Gnomad AMR exome
AF:
0.00632
Gnomad ASJ exome
AF:
0.000100
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000367
Gnomad OTH exome
AF:
0.00365
GnomAD4 exome
AF:
0.00399
AC:
5822
AN:
1460652
Hom.:
363
Cov.:
73
AF XY:
0.00346
AC XY:
2516
AN XY:
726650
show subpopulations
Gnomad4 AFR exome
AF:
0.143
Gnomad4 AMR exome
AF:
0.00684
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000151
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000167
Gnomad4 OTH exome
AF:
0.00840
GnomAD4 genome
AF:
0.0392
AC:
5968
AN:
152354
Hom.:
432
Cov.:
33
AF XY:
0.0377
AC XY:
2811
AN XY:
74498
show subpopulations
Gnomad4 AFR
AF:
0.136
Gnomad4 AMR
AF:
0.0150
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000828
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000309
Gnomad4 OTH
AF:
0.0279
Alfa
AF:
0.0164
Hom.:
73
Bravo
AF:
0.0453
Asia WGS
AF:
0.00606
AC:
21
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000474

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxFeb 18, 2016This 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. -
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 13, 2015p.Val3475Val in exon 32 of PLEC: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 13.1% (544/4152) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs35775257). -
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.78
CADD
Benign
0.43
DANN
Benign
0.90

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.

Other links and lift over

dbSNP: rs35775257; hg19: chr8-144993975; API