8-143918478-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_201384.3(PLEC):​c.11343G>A​(p.Ser3781Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000846 in 1,596,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S3781S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

PLEC
NM_201384.3 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.38

Publications

0 publications found
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 These names were superseded by plectin.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 Gene-Disease associations (from GenCC):
  • epidermolysis bullosa simplex
    Inheritance: AD Classification: STRONG Submitted by: G2P
  • epidermolysis bullosa simplex 5A, Ogna type
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Genomics England PanelApp
  • autosomal recessive limb-girdle muscular dystrophy type 2Q
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
  • congenital myasthenic syndrome
    Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
  • epidermolysis bullosa simplex 5B, with muscular dystrophy
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Genomics England PanelApp
  • epidermolysis bullosa simplex 5C, with pyloric atresia
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • epidermolysis bullosa simplex with nail dystrophy
    Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
  • autosomal recessive limb-girdle muscular dystrophy
    Inheritance: AR Classification: MODERATE Submitted by: ClinGen
  • aplasia cutis congenita
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • cholestasis
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 8-143918478-C-T is Benign according to our data. Variant chr8-143918478-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 386996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-1.38 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLECNM_201384.3 linkc.11343G>A p.Ser3781Ser synonymous_variant Exon 32 of 32 ENST00000345136.8 NP_958786.1 Q15149-4
PLECNM_201378.4 linkc.11301G>A p.Ser3767Ser synonymous_variant Exon 32 of 32 ENST00000356346.7 NP_958780.1 Q15149-9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PLECENST00000345136.8 linkc.11343G>A p.Ser3781Ser synonymous_variant Exon 32 of 32 1 NM_201384.3 ENSP00000344848.3 Q15149-4
PLECENST00000356346.7 linkc.11301G>A p.Ser3767Ser synonymous_variant Exon 32 of 32 1 NM_201378.4 ENSP00000348702.3 Q15149-9

Frequencies

GnomAD3 genomes
AF:
0.000131
AC:
20
AN:
152138
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000655
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:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000107
AC:
23
AN:
214548
AF XY:
0.000102
show subpopulations
Gnomad AFR exome
AF:
0.000328
Gnomad AMR exome
AF:
0.0000956
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000190
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000116
Gnomad OTH exome
AF:
0.000371
GnomAD4 exome
AF:
0.0000797
AC:
115
AN:
1443760
Hom.:
0
Cov.:
56
AF XY:
0.0000711
AC XY:
51
AN XY:
717378
show subpopulations
African (AFR)
AF:
0.0000905
AC:
3
AN:
33144
American (AMR)
AF:
0.000118
AC:
5
AN:
42218
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25820
East Asian (EAS)
AF:
0.0000771
AC:
3
AN:
38900
South Asian (SAS)
AF:
0.0000118
AC:
1
AN:
84664
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
48770
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5742
European-Non Finnish (NFE)
AF:
0.0000914
AC:
101
AN:
1104770
Other (OTH)
AF:
0.0000335
AC:
2
AN:
59732
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.477
Heterozygous variant carriers
0
8
16
25
33
41
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000131
AC:
20
AN:
152256
Hom.:
0
Cov.:
33
AF XY:
0.000148
AC XY:
11
AN XY:
74438
show subpopulations
African (AFR)
AF:
0.0000963
AC:
4
AN:
41542
American (AMR)
AF:
0.000654
AC:
10
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5174
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000882
AC:
6
AN:
68000
Other (OTH)
AF:
0.00
AC:
0
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000460
Hom.:
0
Bravo
AF:
0.0000907
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Jul 06, 2016
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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. -

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
Oct 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.80
CADD
Benign
0.84
DANN
Benign
0.80
PhyloP100
-1.4
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs376719872; hg19: chr8-144992646; API