rs199878792

chr8-143927378-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_201384.3(PLEC):c.3756+32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00847 in 1,609,584 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (4 hom., cov: 35)
  • Exomes 𝑓: 0.0087 (78 hom.)
• Consequence: PLEC NM_201384.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.44

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 These names were superseded by plectin.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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-143927378-C-T is Benign according to our data. Variant chr8-143927378-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00632 (962/152288) while in subpopulation NFE AF= 0.00948 (645/68026). AF 95% confidence interval is 0.00888. There are 4 homozygotes in gnomad4. There are 466 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201378.4	c.3714+32G>A		intron_variant		ENST00000356346.7
PLEC	NM_201384.3	c.3756+32G>A		intron_variant		ENST00000345136.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8	c.3756+32G>A		intron_variant		1	NM_201384.3
PLEC	ENST00000356346.7	c.3714+32G>A		intron_variant		1	NM_201378.4

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 962 AN: 152172 Hom.: 4 Cov.: 35

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00948

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00669 AC: 1591 AN: 237948 Hom.: 15 AF XY: 0.00657 AC XY: 858 AN XY: 130524

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00442

Gnomad EAS exome AF: 0.0000565

Gnomad SAS exome AF: 0.00269

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.00970

Gnomad OTH exome AF: 0.00738

GnomAD4 exome AF: 0.00869 AC: 12665 AN: 1457296 Hom.: 78 Cov.: 35 AF XY: 0.00854 AC XY: 6194 AN XY: 725150

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00564

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00259

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.00974

Gnomad4 OTH exome AF: 0.00759

GnomAD4 genome AF: 0.00632 AC: 962 AN: 152288 Hom.: 4 Cov.: 35 AF XY: 0.00626 AC XY: 466 AN XY: 74458

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0173

Gnomad4 NFE AF: 0.00948

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00649 Hom.: 3

Bravo AF: 0.00530

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.20
Dann	Benign	0.85
RBP_binding_hub_radar		0.85
RBP_regulation_power_radar		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199878792; hg19: chr8-145001546;