rs11786934

Variant names:

• chr8-143922467-G-A
• rs11786934
• NM_201384.3:c.7425+37C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-143922467-G-A
• chr8-143922467-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201384.3(PLEC):​c.7425+37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 1,601,894 control chromosomes in the GnomAD database, including 126,744 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8634 hom., cov: 33)
  • Exomes 𝑓: 0.40 (118110 hom.)
• Consequence: PLEC NM_201384.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.520
• Publications: 12 publications found

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 These names were superseded by plectin.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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 8-143922467-G-A is Benign according to our data. Variant chr8-143922467-G-A is described in ClinVar as [Benign]. Clinvar id is 256177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEC	NM_201384.3	c.7425+37C>T		intron_variant	Intron 31 of 31	ENST00000345136.8	NP_958786.1
PLEC	NM_201378.4	c.7383+37C>T		intron_variant	Intron 31 of 31	ENST00000356346.7	NP_958780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8	c.7425+37C>T		intron_variant	Intron 31 of 31	1	NM_201384.3	ENSP00000344848.3
PLEC	ENST00000356346.7	c.7383+37C>T		intron_variant	Intron 31 of 31	1	NM_201378.4	ENSP00000348702.3

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45968 AN: 151964 Hom.: 8635 Cov.: 33

Gnomad AFR AF: 0.0885

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.342 AC: 81480 AN: 238114 AF XY: 0.355

Gnomad AFR exome AF: 0.0746

Gnomad AMR exome AF: 0.242

Gnomad ASJ exome AF: 0.461

Gnomad EAS exome AF: 0.142

Gnomad FIN exome AF: 0.408

Gnomad NFE exome AF: 0.416

Gnomad OTH exome AF: 0.384

GnomAD4 exome AF: 0.396 AC: 574519 AN: 1449812 Hom.: 118110 Cov.: 77 AF XY: 0.396 AC XY: 285881 AN XY: 721606

African (AFR) AF: 0.0730 AC: 2443 AN: 33474

American (AMR) AF: 0.252 AC: 11287 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 12040 AN: 26136

East Asian (EAS) AF: 0.170 AC: 6766 AN: 39696

South Asian (SAS) AF: 0.361 AC: 31105 AN: 86224

European-Finnish (FIN) AF: 0.397 AC: 16543 AN: 41718

Middle Eastern (MID) AF: 0.402 AC: 2313 AN: 5758

European-Non Finnish (NFE) AF: 0.422 AC: 468884 AN: 1111778

Other (OTH) AF: 0.384 AC: 23138 AN: 60312

GnomAD4 genome AF: 0.302 AC: 45946 AN: 152082 Hom.: 8634 Cov.: 33 AF XY: 0.302 AC XY: 22436 AN XY: 74350

African (AFR) AF: 0.0883 AC: 3667 AN: 41536

American (AMR) AF: 0.306 AC: 4680 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1571 AN: 3464

East Asian (EAS) AF: 0.150 AC: 776 AN: 5166

South Asian (SAS) AF: 0.352 AC: 1694 AN: 4816

European-Finnish (FIN) AF: 0.396 AC: 4190 AN: 10572

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28180 AN: 67938

Other (OTH) AF: 0.329 AC: 692 AN: 2104

Alfa AF: 0.303 Hom.: 1384

Bravo AF: 0.281

Asia WGS AF: 0.221 AC: 768 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: 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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epidermolysis bullosa simplex with nail dystrophy Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epidermolysis bullosa simplex 5C, with pyloric atresia Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epidermolysis bullosa simplex 5B, with muscular dystrophy Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2Q Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epidermolysis bullosa simplex, Ogna type Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: 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	-0.91
CADD	Benign	0.97
DANN	Benign	0.76
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11786934; hg19: chr8-144996635; COSMIC: COSV107382971;