rs80356816

chr12-52515065-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000424.4(KRT5):c.1649del(p.Gly550AlafsTer77) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: KRT5 NM_000424.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:3
• Conservation: PhyloP100: 4.79

Genes affected

KRT5 (HGNC:6442): (keratin 5) The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the basal layer of the epidermis with family member KRT14. Mutations in these genes have been associated with a complex of diseases termed epidermolysis bullosa simplex. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0699 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-52515065-GC-G is Pathogenic according to our data. Variant chr12-52515065-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 14655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-52515065-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT5	NM_000424.4	c.1649del	p.Gly550AlafsTer77	frameshift_variant	9/9	ENST00000252242.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT5	ENST00000252242.9	c.1649del	p.Gly550AlafsTer77	frameshift_variant	9/9	1	NM_000424.4	P1
KRT5	ENST00000552952.1	n.574del		non_coding_transcript_exon_variant	2/2	2
KRT5	ENST00000549511.5			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2020	Frameshift variant predicted to result in protein extension, replacing the last 41 amino acids with an elongated segment of 76 amino acids with different characteristics; Published functional studies demonstrates a damaging effect as in vitro expressed mutant K5 forms much shorter polymers with K14 than wildtype K5 with viscoelastic properties too weak to be reliably measured (Gu et al., 2005); In contrast to the typical hot spot mutations in KRT5 that affect the central rod domain, this variant is predicted to extend the tail domain of keratin 5 and completely alter its composition and physico-chemical properties; the extended tail region has been proposed to interfere with functional interactions between this keratin and its associated proteins (Gu et al., 2005); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20199538, 20055872, 27730678, 24104543, 23993914, 23889190, 15647384, 15982306, 28830826, 15324323, 12925204, 21375516, 32484238, 33274474) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2023	This sequence change results in a frameshift in the KRT5 gene (p.Gly550Alafs*77). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the KRT5 protein and extend the protein by 35 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with autosomal dominant epidermolysis bullosa simplex (PMID: 12925204, 15324323, 24104543). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14655). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects KRT5 function (PMID: 15647384). For these reasons, this variant has been classified as Pathogenic. -
not provided, flagged submission	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Epidermolysis bullosa simplex with migratory circinate erythema Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2004	- -

Epidermolysis bullosa simplex with mottled pigmentation Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2004

- -

Epidermolysis bullosa simplex Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Biomedical Innovation Departament, CIEMAT

Jan 06, 2009

- -

KRT5-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2024

The KRT5 c.1649delG variant is predicted to result in a frameshift and premature protein termination (p.Gly550Alafs*77). This variant is predicted to result in a frameshift and elongation of the protein beyond the normal stop codon (p.Gly550Alafs*77). This variant has been reported as a recurrent finding in individuals with epidermolysis bullosa simplex (see for example, Nagao-Watanabe et al. 2004. PubMed ID: 15324323; Kumagai et al. 2017. PubMed ID: 27730678; Table S1, Chen et al. 2020. PubMed ID: 32484238). It has been documented as a de novo variant, as well as inherited from a mosaic parent. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in KRT5 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs61126080; hg19: chr12-52908849;