NM_201384.3:c.4521C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1

The NM_201384.3(PLEC):c.4521C>T(p.Ser1507Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000559 in 1,590,882 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 (★★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

PLEC
NM_201384.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.199

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 These names were superseded by plectin.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

PLEC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 8-143925408-G-A is Benign according to our data. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143925408-G-A is described in CliVar as Likely_benign. Clinvar id is 284582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.199 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000264 (40/151584) while in subpopulation AFR AF = 0.000824 (34/41250). AF 95% confidence interval is 0.000606. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEC	NM_201384.3 link	c.4521C>T	p.Ser1507Ser	synonymous_variant	Exon 31 of 32	ENST00000345136.8	NP_958786.1	Q15149-4
PLEC	NM_201378.4 link	c.4479C>T	p.Ser1493Ser	synonymous_variant	Exon 31 of 32	ENST00000356346.7	NP_958780.1	Q15149-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8 link	c.4521C>T	p.Ser1507Ser	synonymous_variant	Exon 31 of 32	1	NM_201384.3	ENSP00000344848.3		Q15149-4
PLEC	ENST00000356346.7 link	c.4479C>T	p.Ser1493Ser	synonymous_variant	Exon 31 of 32	1	NM_201378.4	ENSP00000348702.3		Q15149-9

Frequencies

GnomAD3 genomes

AF:

0.000264

AC:

AN:

151584

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000824

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000295

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000999

AC:

AN:

210238

AF XY:

0.0000256

show subpopulations

Gnomad AFR exome

AF:

0.00127

Gnomad AMR exome

AF:

0.0000600

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000555

GnomAD4 exome

AF:

0.0000340

AC:

AN:

1439298

Hom.:

Cov.:

AF XY:

0.0000223

AC XY:

AN XY:

715960

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33286

American (AMR)

AF:

0.000181

AC:

AN:

44134

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25892

East Asian (EAS)

AF:

0.00

AC:

AN:

39424

South Asian (SAS)

AF:

0.00

AC:

AN:

85376

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37430

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1108224

Other (OTH)

AF:

0.0000334

AC:

AN:

59924

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000264

AC:

AN:

151584

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

AN XY:

73992

show subpopulations

African (AFR)

AF:

0.000824

AC:

AN:

41250

American (AMR)

AF:

0.000197

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5108

South Asian (SAS)

AF:

0.00

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67840

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000174

Hom.:

Bravo

AF:

0.000321

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 22, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PLEC-related disorder

Benign:1

Dec 15, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

6.0

(source)

DANN

Benign

0.96

PhyloP100

0.20

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over