rs59115483
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_000424.4(KRT5):c.508G>A(p.Glu170Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E170G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000424.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRT5 | NM_000424.4 | c.508G>A | p.Glu170Lys | missense_variant | 1/9 | ENST00000252242.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRT5 | ENST00000252242.9 | c.508G>A | p.Glu170Lys | missense_variant | 1/9 | 1 | NM_000424.4 | P1 | |
KRT5 | ENST00000552629.5 | n.606G>A | non_coding_transcript_exon_variant | 1/7 | 1 | ||||
KRT5 | ENST00000549420.1 | c.178G>A | p.Glu60Lys | missense_variant | 2/5 | 5 | |||
KRT5 | ENST00000551275.1 | c.403G>A | p.Glu135Lys | missense_variant | 2/2 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152078Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251496Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135922
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727238
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74282
ClinVar
Submissions by phenotype
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2023 | Published functional studies demonstrate a damaging effect due to disruption of keratin intermediate filament alignment and formation, leading to cytoplasmic aggregates and a weakened cytoskeleton (Yasukawa et al., 2002); Located in the highly conserved helix initiation motif of the alpha-helical rod domain, which is intolerant to change; variants in this motif interfere with proper keratin intermediate filament assembly and function, resulting in skin fragility and/or hyperkeratosis (Chamcheu et al., 2011); 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: 20055872, 20030639, 31302245, 26432462, 17549391, 11990248, 21144712, 26707537, 28425111, 31589614, 12707098, 18704110, 16786515, 21176769, 11973334) - |
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Epidermolysis bullosa simplex 2C, localized Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2011 | - - |
KRT5-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 22, 2024 | The KRT5 c.508G>A variant is predicted to result in the amino acid substitution p.Glu170Lys. This variant has been reported in the heterozygous, compound heterozygous, and homozygous states in multiple individuals with epidermolysis bullosa simplex (EBS) (for example, see Yasukawa et al. 2002. PubMed ID: 11973334; Ołdak et al. 2011. PubMed ID: 21144712; Wertheim-Tysarowska et al. 2016. PubMed ID: 26432462; González-Cantero et al. 2017. PubMed ID: 28425111). Fluorescent confocal microscopy of affected patient tissues revealed that this variant leads to increased formation of keratin aggregates and disruption of the epidermal keratin filament network (Yasukawa et al. 2002. PubMed ID: 11973334). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. Of note, another missense variant at the same amino acid position (p.Glu170Gly) has also been reported in a pair of siblings with a EBS phenotype (Rugg et al. 2007. PubMed ID: 17039244). Taken together, the p.Glu170Lys variant is interpreted as pathogenic. - |
Epidermolysis bullosa simplex Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Biomedical Innovation Departament, CIEMAT | Feb 18, 2010 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at