rs6994460

Variant names:

• chr8-143934763-G-C
• rs6994460
• NM_201384.3:c.946-33C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-143934763-G-C
• chr8-143934763-G-T
• chr8-143934763-G-A

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.946-33C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 1,611,652 control chromosomes in the GnomAD database, including 133,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16319 hom., cov: 34)
  • Exomes 𝑓: 0.40 (117363 hom.)
• Consequence: PLEC NM_201384.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.02
• Publications: 14 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 These names were superseded by plectin.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 (BayesDel_noAF=-0.9).
• BP6: Variant 8-143934763-G-C is Benign according to our data. Variant chr8-143934763-G-C is described in ClinVar as Benign. ClinVar VariationId is 256168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.616 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEC	NM_201384.3	MANE Select	c.946-33C>G		intron	N/A	NP_958786.1	Q15149-4
	PLEC	NM_201378.4	MANE Plus Clinical	c.904-33C>G		intron	N/A	NP_958780.1	Q15149-9
	PLEC	NM_201380.4		c.1357-33C>G		intron	N/A	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.946-33C>G		intron	N/A	ENSP00000344848.3	Q15149-4
	PLEC	ENST00000356346.7	TSL:1 MANE Plus Clinical	c.904-33C>G		intron	N/A	ENSP00000348702.3	Q15149-9
	PLEC	ENST00000322810.8	TSL:1	c.1357-33C>G		intron	N/A	ENSP00000323856.4	Q15149-1

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67882 AN: 152014 Hom.: 16278 Cov.: 34

Gnomad AFR AF: 0.622

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.447

GnomAD2 exomes AF: 0.372 AC: 91857 AN: 246654 AF XY: 0.374

Gnomad AFR exome AF: 0.625

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.468

Gnomad EAS exome AF: 0.145

Gnomad FIN exome AF: 0.400

Gnomad NFE exome AF: 0.401

Gnomad OTH exome AF: 0.393

GnomAD4 exome AF: 0.396 AC: 577590 AN: 1459520 Hom.: 117363 Cov.: 52 AF XY: 0.394 AC XY: 285975 AN XY: 726120

African (AFR) AF: 0.637 AC: 21313 AN: 33476

American (AMR) AF: 0.273 AC: 12193 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 12133 AN: 26128

East Asian (EAS) AF: 0.173 AC: 6867 AN: 39694

South Asian (SAS) AF: 0.353 AC: 30446 AN: 86254

European-Finnish (FIN) AF: 0.393 AC: 20138 AN: 51290

Middle Eastern (MID) AF: 0.434 AC: 2505 AN: 5768

European-Non Finnish (NFE) AF: 0.403 AC: 447620 AN: 1111832

Other (OTH) AF: 0.404 AC: 24375 AN: 60362

GnomAD4 genome AF: 0.447 AC: 67961 AN: 152132 Hom.: 16319 Cov.: 34 AF XY: 0.442 AC XY: 32876 AN XY: 74356

African (AFR) AF: 0.622 AC: 25823 AN: 41506

American (AMR) AF: 0.355 AC: 5432 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 1586 AN: 3470

East Asian (EAS) AF: 0.153 AC: 789 AN: 5164

South Asian (SAS) AF: 0.349 AC: 1684 AN: 4828

European-Finnish (FIN) AF: 0.390 AC: 4126 AN: 10590

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27104 AN: 67964

Other (OTH) AF: 0.443 AC: 938 AN: 2116

Alfa AF: 0.330 Hom.: 1359

Bravo AF: 0.449

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.11
DANN	Benign	0.40
PhyloP100		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs6994460; hg19: chr8-145008931; COSMIC: COSV59644859; COSMIC: COSV59644859;