NM_201384.3:c.2923+37C>T

Variant names:

• chr8-143929609-G-A
• rs11136335
• NM_201384.3:c.2923+37C>T

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.2923+37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,609,692 control chromosomes in the GnomAD database, including 118,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (8079 hom., cov: 34)
  • Exomes 𝑓: 0.38 (110454 hom.)
• Consequence: PLEC NM_201384.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.63
• Publications: 25 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 These names were superseded by plectin.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=-0.84).
• BP6: Variant 8-143929609-G-A is Benign according to our data. Variant chr8-143929609-G-A is described in ClinVar as Benign. ClinVar VariationId is 256173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEC	NM_201384.3	c.2923+37C>T		intron_variant	Intron 23 of 31	ENST00000345136.8	NP_958786.1
PLEC	NM_201378.4	c.2881+37C>T		intron_variant	Intron 23 of 31	ENST00000356346.7	NP_958780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8	c.2923+37C>T		intron_variant	Intron 23 of 31	1	NM_201384.3	ENSP00000344848.3
PLEC	ENST00000356346.7	c.2881+37C>T		intron_variant	Intron 23 of 31	1	NM_201378.4	ENSP00000348702.3

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44523 AN: 152006 Hom.: 8081 Cov.: 34

Gnomad AFR AF: 0.0868

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.323

GnomAD2 exomes AF: 0.332 AC: 78814 AN: 237568 AF XY: 0.343

Gnomad AFR exome AF: 0.0750

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.458

Gnomad EAS exome AF: 0.135

Gnomad FIN exome AF: 0.400

Gnomad NFE exome AF: 0.403

Gnomad OTH exome AF: 0.375

GnomAD4 exome AF: 0.382 AC: 557229 AN: 1457568 Hom.: 110454 Cov.: 65 AF XY: 0.383 AC XY: 277484 AN XY: 725264

African (AFR) AF: 0.0703 AC: 2352 AN: 33470

American (AMR) AF: 0.240 AC: 10728 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 11932 AN: 26122

East Asian (EAS) AF: 0.157 AC: 6237 AN: 39678

South Asian (SAS) AF: 0.352 AC: 30331 AN: 86246

European-Finnish (FIN) AF: 0.390 AC: 19318 AN: 49562

Middle Eastern (MID) AF: 0.379 AC: 2188 AN: 5766

European-Non Finnish (NFE) AF: 0.406 AC: 451836 AN: 1111692

Other (OTH) AF: 0.370 AC: 22307 AN: 60342

GnomAD4 genome AF: 0.293 AC: 44497 AN: 152124 Hom.: 8079 Cov.: 34 AF XY: 0.293 AC XY: 21754 AN XY: 74368

African (AFR) AF: 0.0866 AC: 3595 AN: 41536

American (AMR) AF: 0.294 AC: 4488 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1561 AN: 3468

East Asian (EAS) AF: 0.144 AC: 746 AN: 5170

South Asian (SAS) AF: 0.345 AC: 1666 AN: 4826

European-Finnish (FIN) AF: 0.389 AC: 4119 AN: 10592

Middle Eastern (MID) AF: 0.322 AC: 94 AN: 292

European-Non Finnish (NFE) AF: 0.400 AC: 27158 AN: 67942

Other (OTH) AF: 0.320 AC: 676 AN: 2110

Alfa AF: 0.361 Hom.: 3521

Bravo AF: 0.272

Asia WGS AF: 0.216 AC: 753 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	-0.84
CADD	Benign	0.055
DANN	Benign	0.58
PhyloP100		-4.6
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		2.0
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: rs11136335; hg19: chr8-145003777; COSMIC: COSV59651730; COSMIC: COSV59651730;