GeneBe

rs28933087

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_005554.4(KRT6A):​c.520T>G​(p.Phe174Val) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F174C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

KRT6A
NM_005554.4 missense

Scores

15
2
2

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 9.08

Publications

5 publications found
Variant links:
Genes affected
KRT6A (HGNC:6443): (keratin 6A) The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. As many as six of this type II cytokeratin (KRT6) have been identified; the multiplicity of the genes is attributed to successive gene duplication events. The genes are expressed with family members KRT16 and/or KRT17 in the filiform papillae of the tongue, the stratified epithelial lining of oral mucosa and esophagus, the outer root sheath of hair follicles, and the glandular epithelia. This KRT6 gene in particular encodes the most abundant isoform. Mutations in these genes have been associated with pachyonychia congenita. In addition, peptides from the C-terminal region of the protein have antimicrobial activity against bacterial pathogens. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Oct 2014]
KRT6A Gene-Disease associations (from GenCC):
  • pachyonychia congenita 3
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • pachyonychia congenita
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_005554.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-52492668-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 66591.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.934
PP5
Variant 12-52492669-A-C is Pathogenic according to our data. Variant chr12-52492669-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 14635.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KRT6ANM_005554.4 linkc.520T>G p.Phe174Val missense_variant Exon 1 of 9 ENST00000330722.7 NP_005545.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KRT6AENST00000330722.7 linkc.520T>G p.Phe174Val missense_variant Exon 1 of 9 1 NM_005554.4 ENSP00000369317.3
KRT6AENST00000549898.5 linkn.41T>G non_coding_transcript_exon_variant Exon 1 of 5 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1461742
Hom.:
0
Cov.:
75
AF XY:
0.00
AC XY:
0
AN XY:
727182
African (AFR)
AF:
0.00
AC:
0
AN:
33472
American (AMR)
AF:
0.00
AC:
0
AN:
44714
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86248
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111916
Other (OTH)
AF:
0.00
AC:
0
AN:
60382
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Pachyonychia congenita 3 Pathogenic:1
Dec 01, 2001
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

not provided Other:1
-
Epithelial Biology; Institute of Medical Biology, Singapore
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.46
CADD
Uncertain
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.85
D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.97
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.84
T
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.93
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.3
H
PhyloP100
9.1
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-6.2
D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.93
MutPred
0.79
Gain of catalytic residue at I178 (P = 0.0078);
MVP
0.97
MPC
1.1
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.93
gMVP
0.86
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs28933087; hg19: chr12-52886453; API