chr12-52679867-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_006121.4(KRT1):c.482T>C(p.Leu161Pro) 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. 12/21 in silico tools predict a damaging 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. L161F) has been classified as Uncertain significance.
Frequency
Consequence
NM_006121.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRT1 | NM_006121.4 | c.482T>C | p.Leu161Pro | missense_variant | 1/9 | ENST00000252244.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRT1 | ENST00000252244.3 | c.482T>C | p.Leu161Pro | missense_variant | 1/9 | 1 | NM_006121.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 20, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KRT1 function (PMID: 1381288). 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 KRT1 protein function. ClinVar contains an entry for this variant (Variation ID: 15908). This variant is also known as leucine to proline amino acid substitution at codon 160. This missense change has been observed in individual(s) with epidermolytic ichthyosis (PMID: 1284546, 1381288). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 161 of the KRT1 protein (p.Leu161Pro). - |
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Epidermolytic ichthyosis Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 04, 1992 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at