rs62522552

Variant names:

• chr8-143927099-G-A
• rs62522552
• NM_201384.3:c.3841-18C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-143927099-G-A
• chr8-143927099-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_201384.3(PLEC):​c.3841-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,598,542 control chromosomes in the GnomAD database, including 31,574 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2180 hom., cov: 34)
  • Exomes 𝑓: 0.19 (29394 hom.)
• Consequence: PLEC NM_201384.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.35
• Publications: 4 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 These names were superseded by plectin.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=-0.89).
• BP6: Variant 8-143927099-G-A is Benign according to our data. Variant chr8-143927099-G-A is described in ClinVar as Benign. ClinVar VariationId is 256176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEC	NM_201384.3	c.3841-18C>T		intron_variant	Intron 28 of 31	ENST00000345136.8	NP_958786.1
PLEC	NM_201378.4	c.3799-18C>T		intron_variant	Intron 28 of 31	ENST00000356346.7	NP_958780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8	c.3841-18C>T		intron_variant	Intron 28 of 31	1	NM_201384.3	ENSP00000344848.3
PLEC	ENST00000356346.7	c.3799-18C>T		intron_variant	Intron 28 of 31	1	NM_201378.4	ENSP00000348702.3

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22205 AN: 152114 Hom.: 2181 Cov.: 34

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0818

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.156

GnomAD2 exomes AF: 0.154 AC: 37430 AN: 243142 AF XY: 0.157

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.000448

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.193 AC: 278665 AN: 1446310 Hom.: 29394 Cov.: 30 AF XY: 0.190 AC XY: 136505 AN XY: 720314

African (AFR) AF: 0.0297 AC: 986 AN: 33220

American (AMR) AF: 0.108 AC: 4806 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 3427 AN: 26072

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39648

South Asian (SAS) AF: 0.0966 AC: 8306 AN: 86026

European-Finnish (FIN) AF: 0.243 AC: 11792 AN: 48498

Middle Eastern (MID) AF: 0.134 AC: 768 AN: 5740

European-Non Finnish (NFE) AF: 0.216 AC: 237871 AN: 1102538

Other (OTH) AF: 0.178 AC: 10697 AN: 59974

GnomAD4 genome AF: 0.146 AC: 22204 AN: 152232 Hom.: 2180 Cov.: 34 AF XY: 0.144 AC XY: 10686 AN XY: 74408

African (AFR) AF: 0.0384 AC: 1595 AN: 41550

American (AMR) AF: 0.139 AC: 2127 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 447 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5178

South Asian (SAS) AF: 0.0819 AC: 395 AN: 4824

European-Finnish (FIN) AF: 0.249 AC: 2641 AN: 10592

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14411 AN: 67992

Other (OTH) AF: 0.155 AC: 327 AN: 2116

Alfa AF: 0.179 Hom.: 892

Bravo AF: 0.134

Asia WGS AF: 0.0380 AC: 134 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 2016

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, Ogna type;C2677349:Epidermolysis bullosa simplex 5C, with pyloric atresia;C2931072:Epidermolysis bullosa simplex 5B, with muscular dystrophy;C3150989:Autosomal recessive limb-girdle muscular dystrophy type 2Q;C4225309:Epidermolysis bullosa simplex with nail dystrophy Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.8
DANN	Benign	0.53
PhyloP100		-2.4
RBP_binding_hub_radar		0.85
RBP_regulation_power_radar		1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs62522552; hg19: chr8-145001267; COSMIC: COSV59709403; COSMIC: COSV59709403;