chr12-52516647-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000424.4(KRT5):c.1429G>A(p.Glu477Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
KRT5
NM_000424.4 missense
NM_000424.4 missense
Scores
9
9
1
Clinical Significance
Conservation
PhyloP100: 7.78
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 12-52516647-C-T is Pathogenic according to our data. Variant chr12-52516647-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 21174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727228
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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1461868
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31
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0
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727228
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 20, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 477 of the KRT5 protein (p.Glu477Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant epidermolysis bullosa simplex and/or epidermolysis bullosa simplex (PMID: 9036937, 16098032, 26743602, 31579952). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 21174). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KRT5 protein function. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 07, 2023 | Located in the helix termination motif, which is highly conserved across all species and among all members of the keratin family; keratin gene variants affecting the residues at the ends of the central rod domains of the keratin proteins (helix initiation and termination motifs) interfere with proper keratin intermediate filament assembly and function, resulting in skin fragility, blistering, and/or hyperkeratosis (PMID: 21176769); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16601668, 16098032, 28830826, 20030639, 9036937, 28561874, 26743602, 29464779, 31579952, 30515866, 35432467, 36287101, 21176769) - |
| not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Epidermolysis bullosa simplex with mottled pigmentation Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 03, 2019 | Across a selection of literature, the KRT5 c.1429G>A (p.Glu477Lys) missense variant has been reported in a heterozygous state in at least 12 individuals with epidermolysis bullosa simplex (Yasukawa et al. 2006; Jerábková et al. 2010; Sathishkumar et al. 2016; Kim et al. 2017). All patients with this variant were reported to have a severe presentation. The affected parent of one patient was also identified to carry the variant (Sathishkumar et al. 2016). The p.Glu477Lys variant was absent from at least 52 healthy control alleles and is not found in the Genome Aggregation Database. This variant is located in the highly conserved KLLEGE motif. Based on the collective evidence, the p.Glu477Lys variant is classified as pathogenic for epidermolysis bullosa simplex. - |
KRT5-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 29, 2024 | The KRT5 c.1429G>A variant is predicted to result in the amino acid substitution p.Glu477Lys. This variant has been reported in multiple individuals with autosomal dominant epidermolysis bullosa, and in some cases was determined to have arisen de novo (Stephens et al. 1997. PubMed ID: 9036937; Pfendner et al. 2005. PubMed ID: 16098032; Sathishkumar et al. 2016. PubMed ID: 26743602; Vahidnezhad et al. 2017. PubMed ID: 28830826). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. - |
Epidermolysis bullosa simplex 1C, localized Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Epidermolysis bullosa simplex Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Biomedical Innovation Departament, CIEMAT | Feb 01, 2019 | - - |
Epidermolysis bullosa simplex 2A, generalized severe Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 17, 2022 | - - |
Epidermolysis bullosa simplex 1A, generalized severe Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of ubiquitination at E477 (P = 0.0085);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at