8-143927314-G-C

Position:

• chr8-143927314-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_201384.3(PLEC):​c.3778C>G​(p.Arg1260Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000422 in 1,613,124 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 35)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: PLEC NM_201384.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.23

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 These names were superseded by plectin.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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054985285).
• BP6: Variant 8-143927314-G-C is Benign according to our data. Variant chr8-143927314-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 196148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00226 (344/152342) while in subpopulation AFR AF= 0.00801 (333/41572). AF 95% confidence interval is 0.0073. There are 3 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEC	NM_201384.3	c.3778C>G	p.Arg1260Gly	missense_variant	28/32	ENST00000345136.8	NP_958786.1
PLEC	NM_201378.4	c.3736C>G	p.Arg1246Gly	missense_variant	28/32	ENST00000356346.7	NP_958780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8	c.3778C>G	p.Arg1260Gly	missense_variant	28/32	1	NM_201384.3	ENSP00000344848.3
PLEC	ENST00000356346.7	c.3736C>G	p.Arg1246Gly	missense_variant	28/32	1	NM_201378.4	ENSP00000348702.3

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 343 AN: 152224 Hom.: 3 Cov.: 35

Gnomad AFR AF: 0.00801

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000500 AC: 122 AN: 244156 Hom.: 1 AF XY: 0.000406 AC XY: 54 AN XY: 132952

Gnomad AFR exome AF: 0.00764

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000919

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000231 AC: 337 AN: 1460782 Hom.: 1 Cov.: 33 AF XY: 0.000212 AC XY: 154 AN XY: 726688

Gnomad4 AFR exome AF: 0.00789

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152342 Hom.: 3 Cov.: 35 AF XY: 0.00205 AC XY: 153 AN XY: 74504

Gnomad4 AFR AF: 0.00801

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000112 Hom.: 1

Bravo AF: 0.00253

ESP6500AA AF: 0.00535 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000512 AC: 62

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2016	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.66
DEOGEN2	Benign	0.41	.;.;.;.;T;.;.;.;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0055	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;.;.;.;L;.;.;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.0	D;D;D;D;D;D;D;D;.;D
REVEL	Benign	0.071
Sift	Benign	0.34	T;T;T;T;T;T;T;T;.;T
Sift4G	Benign	0.49	T;T;T;T;T;T;T;T;.;T
Polyphen		0.11	B;B;B;B;B;B;B;B;.;.
Vest4		0.55
MVP		0.30
ClinPred		0.041	T
GERP RS		4.0
Varity_R		0.27
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs151022876; hg19: chr8-145001482;