8-143925331-C-T

Variant summary

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

The NM_201384.3(PLEC):​c.4598G>A​(p.Arg1533Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00583 in 1,555,728 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0037 ( 3 hom., cov: 36)
Exomes 𝑓: 0.0061 ( 32 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

1
3
15

Clinical Significance

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

Conservation

PhyloP100: 1.17
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 These names were superseded by plectin.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 -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0071766973).
BP6
Variant 8-143925331-C-T is Benign according to our data. Variant chr8-143925331-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 167510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925331-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00369 (560/151938) while in subpopulation NFE AF= 0.00585 (397/67882). AF 95% confidence interval is 0.00537. There are 3 homozygotes in gnomad4. There are 268 alleles in male gnomad4 subpopulation. Median coverage is 36. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PLECNM_201384.3 linkuse as main transcriptc.4598G>A p.Arg1533Gln missense_variant 31/32 ENST00000345136.8 NP_958786.1 Q15149-4
PLECNM_201378.4 linkuse as main transcriptc.4556G>A p.Arg1519Gln missense_variant 31/32 ENST00000356346.7 NP_958780.1 Q15149-9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PLECENST00000345136.8 linkuse as main transcriptc.4598G>A p.Arg1533Gln missense_variant 31/321 NM_201384.3 ENSP00000344848.3 Q15149-4
PLECENST00000356346.7 linkuse as main transcriptc.4556G>A p.Arg1519Gln missense_variant 31/321 NM_201378.4 ENSP00000348702.3 Q15149-9

Frequencies

GnomAD3 genomes
AF:
0.00369
AC:
560
AN:
151830
Hom.:
3
Cov.:
36
show subpopulations
Gnomad AFR
AF:
0.00116
Gnomad AMI
AF:
0.0121
Gnomad AMR
AF:
0.00328
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.000194
Gnomad SAS
AF:
0.00394
Gnomad FIN
AF:
0.00227
Gnomad MID
AF:
0.00974
Gnomad NFE
AF:
0.00585
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.00407
AC:
639
AN:
156822
Hom.:
2
AF XY:
0.00414
AC XY:
361
AN XY:
87266
show subpopulations
Gnomad AFR exome
AF:
0.000744
Gnomad AMR exome
AF:
0.00199
Gnomad ASJ exome
AF:
0.000120
Gnomad EAS exome
AF:
0.000318
Gnomad SAS exome
AF:
0.00404
Gnomad FIN exome
AF:
0.00149
Gnomad NFE exome
AF:
0.00684
Gnomad OTH exome
AF:
0.00504
GnomAD4 exome
AF:
0.00607
AC:
8516
AN:
1403790
Hom.:
32
Cov.:
75
AF XY:
0.00583
AC XY:
4055
AN XY:
695268
show subpopulations
Gnomad4 AFR exome
AF:
0.000968
Gnomad4 AMR exome
AF:
0.00221
Gnomad4 ASJ exome
AF:
0.000554
Gnomad4 EAS exome
AF:
0.000136
Gnomad4 SAS exome
AF:
0.00417
Gnomad4 FIN exome
AF:
0.00186
Gnomad4 NFE exome
AF:
0.00700
Gnomad4 OTH exome
AF:
0.00514
GnomAD4 genome
AF:
0.00369
AC:
560
AN:
151938
Hom.:
3
Cov.:
36
AF XY:
0.00361
AC XY:
268
AN XY:
74264
show subpopulations
Gnomad4 AFR
AF:
0.00116
Gnomad4 AMR
AF:
0.00327
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.000195
Gnomad4 SAS
AF:
0.00394
Gnomad4 FIN
AF:
0.00227
Gnomad4 NFE
AF:
0.00585
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.00191
Hom.:
1
Bravo
AF:
0.00367
TwinsUK
AF:
0.00782
AC:
29
ALSPAC
AF:
0.00804
AC:
31
ESP6500AA
AF:
0.000727
AC:
2
ESP6500EA
AF:
0.00422
AC:
26
ExAC
AF:
0.00311
AC:
333
Asia WGS
AF:
0.00232
AC:
8
AN:
3466

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsSep 25, 2017- -
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 23, 2020This variant is associated with the following publications: (PMID: 29334134, 29050564) -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2024PLEC: BS2 -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsFeb 05, 2024- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 18, 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 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 27, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.43
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.062
.;.;.;.;T;.;.;.;.
Eigen
Benign
-0.19
Eigen_PC
Benign
-0.044
FATHMM_MKL
Benign
0.54
D
LIST_S2
Uncertain
0.91
D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.44
D
MetaRNN
Benign
0.0072
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.80
T
MutationAssessor
Benign
0.34
.;.;.;.;N;.;.;.;.
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-0.98
N;N;N;N;N;N;N;N;N
REVEL
Benign
0.037
Sift
Benign
0.12
T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.081
T;T;T;T;T;T;T;T;T
Polyphen
0.11
B;B;B;B;B;B;B;B;.
Vest4
0.20
MVP
0.60
ClinPred
0.015
T
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.055
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

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

Other links and lift over

dbSNP: rs201430180; hg19: chr8-144999499; COSMIC: COSV59644209; API