8-143938609-C-G

Variant names:

• chr8-143938609-C-G
• rs7823393
• NM_201384.3:c.174+22G>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.174+22G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,610,558 control chromosomes in the GnomAD database, including 113,874 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7864 hom., cov: 33)
  • Exomes 𝑓: 0.37 (106010 hom.)
• Consequence: PLEC NM_201384.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.239
• 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 These names were superseded by plectin.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=-0.85).
• BP6: Variant 8-143938609-C-G is Benign according to our data. Variant chr8-143938609-C-G is described in ClinVar as Benign. ClinVar VariationId is 256171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEC	NM_201384.3	MANE Select	c.174+22G>C		intron	N/A	NP_958786.1
	PLEC	NM_201378.4	MANE Plus Clinical	c.132+22G>C		intron	N/A	NP_958780.1
	PLEC	NM_201380.4		c.585+22G>C		intron	N/A	NP_958782.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEC	ENST00000345136.8	TSL:1 MANE Select	c.174+22G>C		intron	N/A	ENSP00000344848.3
	PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.132+22G>C		intron	N/A	ENSP00000348702.3
	PLEC	ENST00000322810.8	TSL:1	c.585+22G>C		intron	N/A	ENSP00000323856.4

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44713 AN: 152026 Hom.: 7863 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.329

GnomAD2 exomes AF: 0.331 AC: 82651 AN: 250004 AF XY: 0.341

Gnomad AFR exome AF: 0.0916

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.152

Gnomad FIN exome AF: 0.397

Gnomad NFE exome AF: 0.393

Gnomad OTH exome AF: 0.372

GnomAD4 exome AF: 0.374 AC: 545998 AN: 1458414 Hom.: 106010 Cov.: 33 AF XY: 0.375 AC XY: 271857 AN XY: 725712

African (AFR) AF: 0.0909 AC: 3039 AN: 33432

American (AMR) AF: 0.244 AC: 10911 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 11956 AN: 26110

East Asian (EAS) AF: 0.158 AC: 6272 AN: 39690

South Asian (SAS) AF: 0.346 AC: 29865 AN: 86198

European-Finnish (FIN) AF: 0.390 AC: 20712 AN: 53060

Middle Eastern (MID) AF: 0.389 AC: 2246 AN: 5768

European-Non Finnish (NFE) AF: 0.396 AC: 438914 AN: 1109140

Other (OTH) AF: 0.366 AC: 22083 AN: 60298

GnomAD4 genome AF: 0.294 AC: 44715 AN: 152144 Hom.: 7864 Cov.: 33 AF XY: 0.294 AC XY: 21900 AN XY: 74376

African (AFR) AF: 0.105 AC: 4355 AN: 41512

American (AMR) AF: 0.298 AC: 4552 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1565 AN: 3472

East Asian (EAS) AF: 0.151 AC: 780 AN: 5174

South Asian (SAS) AF: 0.343 AC: 1653 AN: 4824

European-Finnish (FIN) AF: 0.389 AC: 4121 AN: 10596

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26537 AN: 67948

Other (OTH) AF: 0.326 AC: 690 AN: 2114

Alfa AF: 0.285 Hom.: 1020

Bravo AF: 0.287

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.

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.1
DANN	Benign	0.45
PhyloP100		0.24
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: rs7823393; hg19: chr8-145012777; COSMIC: COSV59615970;