rs11786903

Variant names:

• chr8-143922430-G-A
• rs11786903
• NM_201384.3:c.7426-35C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-143922430-G-A
• chr8-143922430-G-T

Variant summary

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

The NM_201380.4(PLEC):​c.7837-35C>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 1,600,110 control chromosomes in the GnomAD database, including 126,576 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8625 hom., cov: 33)
  • Exomes 𝑓: 0.40 (117951 hom.)
• Consequence: PLEC NM_201380.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.00500
• Publications: 14 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 These names were superseded by plectin.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 8-143922430-G-A is Benign according to our data. Variant chr8-143922430-G-A is described in ClinVar as Benign. ClinVar VariationId is 256178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201380.4. 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.7426-35C>T		intron	N/A	NP_958786.1
	PLEC	NM_201378.4	MANE Plus Clinical	c.7384-35C>T		intron	N/A	NP_958780.1
	PLEC	NM_201380.4		c.7837-35C>T		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.7426-35C>T		intron	N/A	ENSP00000344848.3
	PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.7384-35C>T		intron	N/A	ENSP00000348702.3
	PLEC	ENST00000322810.8	TSL:1	c.7837-35C>T		intron	N/A	ENSP00000323856.4

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45947 AN: 152024 Hom.: 8626 Cov.: 33

Gnomad AFR AF: 0.0883

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.342 AC: 80947 AN: 236548 AF XY: 0.354

Gnomad AFR exome AF: 0.0743

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.143

Gnomad FIN exome AF: 0.410

Gnomad NFE exome AF: 0.416

Gnomad OTH exome AF: 0.383

GnomAD4 exome AF: 0.396 AC: 573769 AN: 1447966 Hom.: 117951 Cov.: 80 AF XY: 0.396 AC XY: 285540 AN XY: 720688

African (AFR) AF: 0.0728 AC: 2437 AN: 33476

American (AMR) AF: 0.252 AC: 11286 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 12038 AN: 26132

East Asian (EAS) AF: 0.170 AC: 6764 AN: 39696

South Asian (SAS) AF: 0.361 AC: 31142 AN: 86240

European-Finnish (FIN) AF: 0.397 AC: 15811 AN: 39822

Middle Eastern (MID) AF: 0.402 AC: 2312 AN: 5758

European-Non Finnish (NFE) AF: 0.422 AC: 468844 AN: 1111824

Other (OTH) AF: 0.384 AC: 23135 AN: 60306

GnomAD4 genome AF: 0.302 AC: 45925 AN: 152144 Hom.: 8625 Cov.: 33 AF XY: 0.302 AC XY: 22426 AN XY: 74376

African (AFR) AF: 0.0881 AC: 3658 AN: 41532

American (AMR) AF: 0.306 AC: 4675 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 1573 AN: 3472

East Asian (EAS) AF: 0.151 AC: 780 AN: 5172

South Asian (SAS) AF: 0.352 AC: 1700 AN: 4826

European-Finnish (FIN) AF: 0.395 AC: 4186 AN: 10590

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

European-Non Finnish (NFE) AF: 0.414 AC: 28160 AN: 67952

Other (OTH) AF: 0.329 AC: 695 AN: 2110

Alfa AF: 0.364 Hom.: 3553

Bravo AF: 0.281

Asia WGS AF: 0.221 AC: 769 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2Q (1)
-	-	1	Epidermolysis bullosa simplex 5B, with muscular dystrophy (1)
-	-	1	Epidermolysis bullosa simplex 5C, with pyloric atresia (1)
-	-	1	Epidermolysis bullosa simplex with nail dystrophy (1)
-	-	1	Epidermolysis bullosa simplex, Ogna type (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.1
DANN	Benign	0.76
PhyloP100		-0.0050
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs11786903; hg19: chr8-144996598; COSMIC: COSV107382970;