chr12-52515065-GC-G

Variant names:

• chr12-52515065-GC-G
• rs61126080
• NM_000424.4:c.1649delG

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.1649delG​(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 rank	MANE	Protein	UniProt
KRT5	NM_000424.4	c.1649delG	p.Gly550AlafsTer77	frameshift_variant	Exon 9 of 9	ENST00000252242.9	NP_000415.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT5	ENST00000252242.9	c.1649delG	p.Gly550AlafsTer77	frameshift_variant	Exon 9 of 9	1	NM_000424.4	ENSP00000252242.4
KRT5	ENST00000552952.1	n.574delG		non_coding_transcript_exon_variant	Exon 2 of 2	2
KRT5	ENST00000549511.5	n.*47delG		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

Aug 24, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Mar 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: flagged submission

Collection Method: literature only

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Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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

Sep 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Epidermolysis bullosa simplex with mottled pigmentation Pathogenic:1

Sep 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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KRT5-related disorder Pathogenic:1

Feb 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Epidermolysis bullosa simplex Pathogenic:1

Jan 06, 2009

Biomedical Innovation Departament, CIEMAT

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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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;