chr12-52646750-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000423.3(KRT2):c.1459G>A(p.Glu487Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 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. E487D) has been classified as Pathogenic.
Frequency
Consequence
NM_000423.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRT2 | NM_000423.3 | c.1459G>A | p.Glu487Lys | missense_variant | 7/9 | ENST00000309680.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRT2 | ENST00000309680.4 | c.1459G>A | p.Glu487Lys | missense_variant | 7/9 | 1 | NM_000423.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461846Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727216
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2Other:1
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 14, 2023 | For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt KRT2 protein function. ClinVar contains an entry for this variant (Variation ID: 9310). This missense change has been observed in individuals with epidermolytic ichthyosis (PMID: 26581228, 29444371, 31953843). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 487 of the KRT2 protein (p.Glu487Lys). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 01, 2022 | Located within the highly conserved helix termination motif (2B) of the rod domain of keratin 2, a well-known mutational hot spot region that is intolerant to change; Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29171394, 29444371, 26581228, 10688369, 10233323, 31953843, 33081034, 32881395, 7524919, 24077912) - |
Ichthyosis bullosa of Siemens Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 1999 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Exfoliative ichthyosis Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 1999 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at