chr8-143922662-C-T

Variant names:

• chr8-143922662-C-T
• rs193257576
• NM_201384.3:c.7267G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_201384.3(PLEC):​c.7267G>A​(p.Ala2423Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00498 in 1,613,304 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (26 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.189
• Publications: 13 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 These names were superseded by plectin.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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006071478).
• BP6: Variant 8-143922662-C-T is Benign according to our data. Variant chr8-143922662-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196716.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00312 (475/152304) while in subpopulation NFE AF = 0.0057 (388/68020). AF 95% confidence interval is 0.00524. There are 0 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 26 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.7267G>A	p.Ala2423Thr	missense	Exon 31 of 32	NP_958786.1	Q15149-4
	PLEC	NM_201378.4	MANE Plus Clinical	c.7225G>A	p.Ala2409Thr	missense	Exon 31 of 32	NP_958780.1	Q15149-9
	PLEC	NM_201380.4		c.7678G>A	p.Ala2560Thr	missense	Exon 31 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.7267G>A	p.Ala2423Thr	missense	Exon 31 of 32	ENSP00000344848.3	Q15149-4
	PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.7225G>A	p.Ala2409Thr	missense	Exon 31 of 32	ENSP00000348702.3	Q15149-9
	PLEC	ENST00000322810.8	TSL:1	c.7678G>A	p.Ala2560Thr	missense	Exon 31 of 32	ENSP00000323856.4	Q15149-1

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00572

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00279 AC: 691 AN: 247382 AF XY: 0.00288

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.000902

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000948

Gnomad FIN exome AF: 0.000987

Gnomad NFE exome AF: 0.00503

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.00517 AC: 7560 AN: 1461000 Hom.: 26 Cov.: 70 AF XY: 0.00498 AC XY: 3618 AN XY: 726770

African (AFR) AF: 0.00116 AC: 39 AN: 33478

American (AMR) AF: 0.000940 AC: 42 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39696

South Asian (SAS) AF: 0.000847 AC: 73 AN: 86158

European-Finnish (FIN) AF: 0.00108 AC: 57 AN: 52890

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5704

European-Non Finnish (NFE) AF: 0.00636 AC: 7072 AN: 1111894

Other (OTH) AF: 0.00426 AC: 257 AN: 60372

GnomAD4 genome AF: 0.00312 AC: 475 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.00281 AC XY: 209 AN XY: 74484

African (AFR) AF: 0.00120 AC: 50 AN: 41570

American (AMR) AF: 0.00124 AC: 19 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5170

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00570 AC: 388 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00441 Hom.: 1

Bravo AF: 0.00298

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00206 AC: 9

ESP6500EA AF: 0.00572 AC: 49

ExAC AF: 0.00289 AC: 350

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00529

EpiControl AF: 0.00599

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	1	1	not specified (2)
-	-	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	PLEC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.19
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.094
Sift	Uncertain	0.024	D
Sift4G	Benign	0.23	T
Polyphen		0.0080	B
Vest4		0.24
MVP		0.39
ClinPred		0.0050	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.037
gMVP		0.29
Mutation Taster		=99/1	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: rs193257576; hg19: chr8-144996830; COSMIC: COSV59636180;