rs138924815

Variant names:

• chr8-143934868-C-T
• rs138924815
• NM_201384.3:c.887G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-143934868-C-T
• chr8-143934868-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_201384.3(PLEC):​c.887G>A​(p.Arg296Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0143 in 1,611,316 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts 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. R296G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (14 hom., cov: 33)
  • Exomes 𝑓: 0.015 (182 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.91
• Publications: 21 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 These names were superseded by plectin.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):

• PLEC-related muscular dystrophy-epidermolysis bullosa simplex spectrum disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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), Genomics England PanelApp, Orphanet
• autosomal recessive limb-girdle muscular dystrophy type 2Q

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• 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: Genomics England PanelApp, Orphanet
• epidermolysis bullosa simplex 5C, with pyloric atresia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• 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=0.0072270334).
• BP6: Variant 8-143934868-C-T is Benign according to our data. Variant chr8-143934868-C-T is described in ClinVar as Benign. ClinVar VariationId is 129963.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 = 0.011 (1683/152318) while in subpopulation NFE AF = 0.0182 (1241/68024). AF 95% confidence interval is 0.0174. There are 14 homozygotes in GnomAd4. There are 790 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEC	NM_201384.3	MANE Select	c.887G>A	p.Arg296Gln	missense	Exon 9 of 32	NP_958786.1	Q15149-4
	PLEC	NM_201378.4	MANE Plus Clinical	c.845G>A	p.Arg282Gln	missense	Exon 9 of 32	NP_958780.1	Q15149-9
	PLEC	NM_201380.4		c.1298G>A	p.Arg433Gln	missense	Exon 9 of 32	NP_958782.1	Q15149-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEC	ENST00000345136.8	TSL:1 MANE Select	c.887G>A	p.Arg296Gln	missense	Exon 9 of 32	ENSP00000344848.3	Q15149-4
	PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.845G>A	p.Arg282Gln	missense	Exon 9 of 32	ENSP00000348702.3	Q15149-9
	PLEC	ENST00000322810.8	TSL:1	c.1298G>A	p.Arg433Gln	missense	Exon 9 of 32	ENSP00000323856.4	Q15149-1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1684 AN: 152200 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.0118 AC: 2870 AN: 242662 AF XY: 0.0120

Gnomad AFR exome AF: 0.00305

Gnomad AMR exome AF: 0.00935

Gnomad ASJ exome AF: 0.0132

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00281

Gnomad NFE exome AF: 0.0188

Gnomad OTH exome AF: 0.0190

GnomAD4 exome AF: 0.0147 AC: 21436 AN: 1458998 Hom.: 182 Cov.: 35 AF XY: 0.0148 AC XY: 10711 AN XY: 725874

African (AFR) AF: 0.00227 AC: 76 AN: 33472

American (AMR) AF: 0.0104 AC: 465 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 323 AN: 26102

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.00557 AC: 480 AN: 86228

European-Finnish (FIN) AF: 0.00304 AC: 155 AN: 51022

Middle Eastern (MID) AF: 0.0310 AC: 179 AN: 5768

European-Non Finnish (NFE) AF: 0.0170 AC: 18923 AN: 1111736

Other (OTH) AF: 0.0138 AC: 833 AN: 60322

GnomAD4 genome AF: 0.0110 AC: 1683 AN: 152318 Hom.: 14 Cov.: 33 AF XY: 0.0106 AC XY: 790 AN XY: 74472

African (AFR) AF: 0.00315 AC: 131 AN: 41572

American (AMR) AF: 0.0112 AC: 172 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4826

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10620

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0182 AC: 1241 AN: 68024

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.0124 Hom.: 14

Bravo AF: 0.0115

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00334 AC: 14

ESP6500EA AF: 0.0170 AC: 144

ExAC AF: 0.0115 AC: 1392

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0203

EpiControl AF: 0.0214

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Epidermolysis bullosa simplex 5B, with muscular 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.9
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.40
ClinPred		0.027	T
GERP RS		4.6
Varity_R		0.46
gMVP		0.42
Mutation Taster		=94/6	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: rs138924815; hg19: chr8-145009036; COSMIC: COSV99052378; COSMIC: COSV99052378;