NM_201384.3:c.7960T>C

Variant names:

• chr8-143921861-A-G
• rs7833924
• NM_201384.3:c.7960T>C

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.7960T>C​(p.Ser2654Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 1,602,450 control chromosomes in the GnomAD database, including 158,379 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (23565 hom., cov: 35)
  • Exomes 𝑓: 0.42 (134814 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.620
• Publications: 46 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 These names were superseded by plectin.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 (MetaRNN=6.375856E-7).
• BP6: Variant 8-143921861-A-G is Benign according to our data. Variant chr8-143921861-A-G is described in ClinVar as Benign. ClinVar VariationId is 93083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.818 is higher than 0.05.

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.7960T>C	p.Ser2654Pro	missense	Exon 32 of 32	NP_958786.1
	PLEC	NM_201378.4	MANE Plus Clinical	c.7918T>C	p.Ser2640Pro	missense	Exon 32 of 32	NP_958780.1
	PLEC	NM_201380.4		c.8371T>C	p.Ser2791Pro	missense	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.7960T>C	p.Ser2654Pro	missense	Exon 32 of 32	ENSP00000344848.3
	PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.7918T>C	p.Ser2640Pro	missense	Exon 32 of 32	ENSP00000348702.3
	PLEC	ENST00000322810.8	TSL:1	c.8371T>C	p.Ser2791Pro	missense	Exon 32 of 32	ENSP00000323856.4

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78817 AN: 152072 Hom.: 23529 Cov.: 35

Gnomad AFR AF: 0.825

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.464

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.491

GnomAD2 exomes AF: 0.398 AC: 91147 AN: 229116 AF XY: 0.397

Gnomad AFR exome AF: 0.834

Gnomad AMR exome AF: 0.282

Gnomad ASJ exome AF: 0.472

Gnomad EAS exome AF: 0.144

Gnomad FIN exome AF: 0.407

Gnomad NFE exome AF: 0.423

Gnomad OTH exome AF: 0.415

GnomAD4 exome AF: 0.423 AC: 612830 AN: 1450260 Hom.: 134814 Cov.: 76 AF XY: 0.419 AC XY: 302622 AN XY: 721952

African (AFR) AF: 0.842 AC: 28178 AN: 33460

American (AMR) AF: 0.298 AC: 13291 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 12243 AN: 26074

East Asian (EAS) AF: 0.175 AC: 6947 AN: 39678

South Asian (SAS) AF: 0.363 AC: 31263 AN: 86198

European-Finnish (FIN) AF: 0.398 AC: 17080 AN: 42910

Middle Eastern (MID) AF: 0.446 AC: 2557 AN: 5728

European-Non Finnish (NFE) AF: 0.427 AC: 474934 AN: 1111344

Other (OTH) AF: 0.437 AC: 26337 AN: 60268

GnomAD4 genome AF: 0.518 AC: 78890 AN: 152190 Hom.: 23565 Cov.: 35 AF XY: 0.510 AC XY: 37975 AN XY: 74398

African (AFR) AF: 0.825 AC: 34305 AN: 41578

American (AMR) AF: 0.394 AC: 6022 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 1609 AN: 3468

East Asian (EAS) AF: 0.153 AC: 792 AN: 5168

South Asian (SAS) AF: 0.355 AC: 1714 AN: 4824

European-Finnish (FIN) AF: 0.398 AC: 4215 AN: 10580

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28681 AN: 67960

Other (OTH) AF: 0.487 AC: 1029 AN: 2114

Alfa AF: 0.451 Hom.: 8584

Bravo AF: 0.528

TwinsUK AF: 0.431 AC: 1598

ALSPAC AF: 0.432 AC: 1665

ESP6500AA AF: 0.826 AC: 3507

ESP6500EA AF: 0.431 AC: 3635

ExAC AF: 0.405 AC: 48551

Asia WGS AF: 0.272 AC: 948 AN: 3478

EpiCase AF: 0.435

EpiControl AF: 0.443

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	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 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.85
DEOGEN2	Benign	0.065	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	6.4e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.38	N
PhyloP100		0.62
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	0.98	T
Polyphen		0.0	B
Vest4		0.11
ClinPred		0.0010	T
GERP RS		1.3
Varity_R		0.24
gMVP		0.71
Mutation Taster		=98/2	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: rs7833924; hg19: chr8-144996029; COSMIC: COSV59631885; COSMIC: COSV59631885;