NM_201384.3:c.6314C>T

Variant names:

• chr8-143923615-G-A
• rs74772299
• NM_201384.3:c.6314C>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.6314C>T​(p.Ala2105Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0463 in 1,589,866 control chromosomes in the GnomAD database, including 2,568 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2105M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.041 (209 hom., cov: 34)
  • Exomes 𝑓: 0.047 (2359 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.30

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 These names were superseded by plectin.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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016222).
• BP6: Variant 8-143923615-G-A is Benign according to our data. Variant chr8-143923615-G-A is described in ClinVar as [Benign]. Clinvar id is 93072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923615-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEC	NM_201384.3	c.6314C>T	p.Ala2105Val	missense_variant	Exon 31 of 32	ENST00000345136.8	NP_958786.1
PLEC	NM_201378.4	c.6272C>T	p.Ala2091Val	missense_variant	Exon 31 of 32	ENST00000356346.7	NP_958780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8	c.6314C>T	p.Ala2105Val	missense_variant	Exon 31 of 32	1	NM_201384.3	ENSP00000344848.3
PLEC	ENST00000356346.7	c.6272C>T	p.Ala2091Val	missense_variant	Exon 31 of 32	1	NM_201378.4	ENSP00000348702.3

Frequencies

GnomAD3 genomes AF: 0.0411 AC: 6207 AN: 150992 Hom.: 206 Cov.: 34

Gnomad AFR AF: 0.00789

Gnomad AMI AF: 0.0178

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0514

Gnomad EAS AF: 0.0368

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.0578

GnomAD2 exomes AF: 0.0675 AC: 14161 AN: 209930 AF XY: 0.0677

Gnomad AFR exome AF: 0.00667

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.0513

Gnomad EAS exome AF: 0.0230

Gnomad FIN exome AF: 0.0367

Gnomad NFE exome AF: 0.0391

Gnomad OTH exome AF: 0.0623

GnomAD4 exome AF: 0.0468 AC: 67334 AN: 1438758 Hom.: 2359 Cov.: 83 AF XY: 0.0493 AC XY: 35296 AN XY: 715724

African (AFR) AF: 0.00729 AC: 242 AN: 33178

American (AMR) AF: 0.144 AC: 6337 AN: 44064

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 1268 AN: 25894

East Asian (EAS) AF: 0.0446 AC: 1748 AN: 39206

South Asian (SAS) AF: 0.132 AC: 11261 AN: 85478

European-Finnish (FIN) AF: 0.0377 AC: 1426 AN: 37856

Middle Eastern (MID) AF: 0.0456 AC: 243 AN: 5332

European-Non Finnish (NFE) AF: 0.0377 AC: 41794 AN: 1108036

Other (OTH) AF: 0.0505 AC: 3015 AN: 59714

GnomAD4 genome AF: 0.0411 AC: 6215 AN: 151108 Hom.: 209 Cov.: 34 AF XY: 0.0437 AC XY: 3227 AN XY: 73790

African (AFR) AF: 0.00786 AC: 323 AN: 41076

American (AMR) AF: 0.107 AC: 1637 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.0514 AC: 178 AN: 3460

East Asian (EAS) AF: 0.0371 AC: 189 AN: 5088

South Asian (SAS) AF: 0.137 AC: 654 AN: 4774

European-Finnish (FIN) AF: 0.0365 AC: 383 AN: 10502

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0399 AC: 2701 AN: 67686

Other (OTH) AF: 0.0572 AC: 120 AN: 2098

Alfa AF: 0.0368 Hom.: 66

Bravo AF: 0.0434

TwinsUK AF: 0.0418 AC: 155

ALSPAC AF: 0.0418 AC: 161

ESP6500AA AF: 0.00876 AC: 31

ESP6500EA AF: 0.0372 AC: 285

ExAC AF: 0.0587 AC: 6773

Asia WGS AF: 0.0890 AC: 307 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala2242Val in exon 31 of PLEC: This variant is not expected to have clinical s ignificance because it has been identified in 3.7% (285/7654) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs74772299). -

Aug 26, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 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
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.18	.;.;.;.;T;.;.;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0016	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	.;.;.;.;M;.;.;.;.
PhyloP100		2.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.020	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D
Polyphen		0.23	B;B;B;B;B;B;B;B;.
Vest4		0.092
ClinPred		0.010	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.031
gMVP		0.34
Mutation Taster		=99/1	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

Publications

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Other links and lift over

dbSNP: rs74772299; hg19: chr8-144997783; COSMIC: COSV59631693;