rs199651668

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS1_Supporting

The NM_201384.3(PLEC):​c.12992C>T​(p.Pro4331Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,612,914 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

10
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 7.83
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 These names were superseded by plectin.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 Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.29439747).
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000162 (237/1460778) while in subpopulation MID AF= 0.0026 (15/5768). AF 95% confidence interval is 0.0016. There are 1 homozygotes in gnomad4_exome. There are 128 alleles in male gnomad4_exome subpopulation. Median coverage is 46. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PLECNM_201384.3 linkuse as main transcriptc.12992C>T p.Pro4331Leu missense_variant 32/32 ENST00000345136.8 NP_958786.1
PLECNM_201378.4 linkuse as main transcriptc.12950C>T p.Pro4317Leu missense_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.12992C>T p.Pro4331Leu missense_variant 32/321 NM_201384.3 ENSP00000344848 Q15149-4
PLECENST00000356346.7 linkuse as main transcriptc.12950C>T p.Pro4317Leu missense_variant 32/321 NM_201378.4 ENSP00000348702 Q15149-9

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152136
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000141
AC:
35
AN:
248644
Hom.:
0
AF XY:
0.000170
AC XY:
23
AN XY:
135218
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000348
Gnomad ASJ exome
AF:
0.0000996
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000151
Gnomad OTH exome
AF:
0.000496
GnomAD4 exome
AF:
0.000162
AC:
237
AN:
1460778
Hom.:
1
Cov.:
46
AF XY:
0.000176
AC XY:
128
AN XY:
726718
show subpopulations
Gnomad4 AFR exome
AF:
0.000777
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000152
Gnomad4 OTH exome
AF:
0.000265
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152136
Hom.:
1
Cov.:
33
AF XY:
0.000121
AC XY:
9
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.0000966
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000201
Hom.:
0
Bravo
AF:
0.000147
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.000173
AC:
21
EpiCase
AF:
0.000164
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:5
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJan 06, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 09, 2019In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsJan 13, 2021- -
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 15, 2015- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 27, 2022The c.13073C>T (p.P4358L) alteration is located in exon 33 (coding exon 32) of the PLEC gene. This alteration results from a C to T substitution at nucleotide position 13073, causing the proline (P) at amino acid position 4358 to be replaced by a leucine (L). 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 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 12, 2023This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4358 of the PLEC protein (p.Pro4358Leu). This variant is present in population databases (rs199651668, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PLEC-related conditions. ClinVar contains an entry for this variant (Variation ID: 196854). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLEC protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
PLEC-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 09, 2024The PLEC c.13073C>T variant is predicted to result in the amino acid substitution p.Pro4358Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.034% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Autosomal recessive limb-girdle muscular dystrophy type 2Q Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaFeb 22, 2019This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP1. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.19
CADD
Uncertain
24
DANN
Benign
0.86
DEOGEN2
Benign
0.075
.;.;.;.;T;.;.;.;.;.
Eigen
Benign
0.19
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.088
D
MetaRNN
Benign
0.29
T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.23
T
MutationAssessor
Uncertain
2.8
.;.;.;.;M;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D
PrimateAI
Benign
0.48
T
PROVEAN
Uncertain
-2.5
D;N;N;D;D;D;D;D;.;D
REVEL
Uncertain
0.39
Sift
Uncertain
0.021
D;D;D;D;D;D;D;D;.;D
Sift4G
Uncertain
0.016
D;D;D;D;D;D;D;D;.;D
Polyphen
0.18
B;B;B;B;B;B;B;B;.;.
Vest4
0.42
MutPred
0.61
.;.;.;.;Loss of disorder (P = 0.0476);.;.;.;.;.;
MVP
0.64
ClinPred
0.13
T
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.9
Varity_R
0.10
gMVP
0.70

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: rs199651668; hg19: chr8-144990997; COSMIC: COSV59639038; API