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

Genomes: not found (cov: 32)

Consequence

KRT16
NM_005557.4 missense

Scores

13
3
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.63
Variant links:
Genes affected
KRT16 (HGNC:6423): (keratin 16) The protein encoded by this gene is a member of the keratin gene family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins. Most of the type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains and are clustered in a region of chromosome 17q12-q21. This keratin has been coexpressed with keratin 14 in a number of epithelial tissues, including esophagus, tongue, and hair follicles. Mutations in this gene are associated with type 1 pachyonychia congenita, non-epidermolytic palmoplantar keratoderma and unilateral palmoplantar verrucous nevus. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a region_of_interest Coil 1A (size 35) in uniprot entity K1C16_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_005557.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-41612310-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 17-41612310-G-C is Pathogenic according to our data. Variant chr17-41612310-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 265217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41612310-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KRT16NM_005557.4 linkc.379C>G p.Arg127Gly missense_variant Exon 1 of 8 ENST00000301653.9 NP_005548.2 P08779

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KRT16ENST00000301653.9 linkc.379C>G p.Arg127Gly missense_variant Exon 1 of 8 1 NM_005557.4 ENSP00000301653.3 P08779
KRT16ENST00000593067.1 linkc.-312-24C>G intron_variant Intron 1 of 6 3 ENSP00000467124.1 K7ENW6
KRT16ENST00000588319.1 linkn.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

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Mar 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

May 11, 2015
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Apr 25, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.47
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.70
T
M_CAP
Pathogenic
0.32
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.8
H
PrimateAI
Benign
0.44
T
PROVEAN
Pathogenic
-6.3
D
REVEL
Pathogenic
0.99
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.94
MutPred
0.96
Loss of stability (P = 0.0141);
MVP
0.93
MPC
1.2
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.95
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs59856285; hg19: chr17-39768562; API