8-143921376-A-G

Variant names:

• chr8-143921376-A-G
• rs371421350
• NM_201384.3:c.8445T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_201384.3(PLEC):​c.8445T>C​(p.Val2815Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,613,324 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V2815V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 34)
  • Exomes 𝑓: 0.00084 (5 hom.)
• Consequence: PLEC NM_201384.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.79
• Publications: 0 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 These names were superseded by plectin.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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 8-143921376-A-G is Benign according to our data. Variant chr8-143921376-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0037 (563/152288) while in subpopulation AFR AF = 0.012 (497/41570). AF 95% confidence interval is 0.0111. There are 4 homozygotes in GnomAd4. There are 273 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.8445T>C	p.Val2815Val	synonymous	Exon 32 of 32	NP_958786.1
	PLEC	NM_201378.4	MANE Plus Clinical	c.8403T>C	p.Val2801Val	synonymous	Exon 32 of 32	NP_958780.1
	PLEC	NM_201380.4		c.8856T>C	p.Val2952Val	synonymous	Exon 32 of 32	NP_958782.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEC	ENST00000345136.8	TSL:1 MANE Select	c.8445T>C	p.Val2815Val	synonymous	Exon 32 of 32	ENSP00000344848.3
	PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.8403T>C	p.Val2801Val	synonymous	Exon 32 of 32	ENSP00000348702.3
	PLEC	ENST00000322810.8	TSL:1	c.8856T>C	p.Val2952Val	synonymous	Exon 32 of 32	ENSP00000323856.4

Frequencies

GnomAD3 genomes AF: 0.00367 AC: 558 AN: 152170 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00118 AC: 292 AN: 247980 AF XY: 0.00105

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000871

Gnomad ASJ exome AF: 0.00180

Gnomad EAS exome AF: 0.0000560

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000453

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000842 AC: 1230 AN: 1461036 Hom.: 5 Cov.: 120 AF XY: 0.000779 AC XY: 566 AN XY: 726830

African (AFR) AF: 0.0113 AC: 378 AN: 33470

American (AMR) AF: 0.000917 AC: 41 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26094

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39690

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86196

European-Finnish (FIN) AF: 0.0000755 AC: 4 AN: 52966

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.000582 AC: 647 AN: 1111786

Other (OTH) AF: 0.00147 AC: 89 AN: 60378

GnomAD4 genome AF: 0.00370 AC: 563 AN: 152288 Hom.: 4 Cov.: 34 AF XY: 0.00367 AC XY: 273 AN XY: 74466

African (AFR) AF: 0.0120 AC: 497 AN: 41570

American (AMR) AF: 0.00190 AC: 29 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000374 Hom.: 0

Bravo AF: 0.00409

EpiCase AF: 0.000763

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Apr 15, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 06, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

May 26, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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;C5676875:Junctional epidermolysis bullosa with pyloric atresia Benign:1

Sep 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	-0.70
CADD	Benign	1.6
DANN	Benign	0.51
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs371421350; hg19: chr8-144995544;