17-41612310-G-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_005557.4(KRT16):c.379C>G(p.Arg127Gly) variant causes a missense change. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127C) has been classified as Pathogenic.
Frequency
Consequence
NM_005557.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KRT16 | ENST00000301653.9 | c.379C>G | p.Arg127Gly | missense_variant | Exon 1 of 8 | 1 | NM_005557.4 | ENSP00000301653.3 | ||
KRT16 | ENST00000593067.1 | c.-312-24C>G | intron_variant | Intron 1 of 6 | 3 | ENSP00000467124.1 | ||||
KRT16 | ENST00000588319.1 | n.456C>G | non_coding_transcript_exon_variant | Exon 1 of 1 | 6 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 127 of the KRT16 protein (p.Arg127Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pachyonychia congenita (PMID: 24611874; Invitae). ClinVar contains an entry for this variant (Variation ID: 265217). 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 KRT16 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg127 amino acid residue in KRT16. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8595410, 31823354). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
The R127G variant has been reported in association with pachyonychia congenita (Wilson et al., 2014; Cao et al., 2015). The R127G variant is a non-conservative amino acid change and located in a highly conserved region coding for the helix initiation motif of keratin 16, a known hotspot. According to the Human Gene Mutation Database (HGMD), many other variants at this residue (R127C, R127S, R127P, R127H) have been reported in association with KRT16-related disorders (Stenson et al., 2014). Moreover, R127G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. -
Pachyonychia congenita 1;C4552049:Palmoplantar keratoderma, nonepidermolytic, focal 1 Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at