rs59151893

chr17-41624235-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM5 PP3 PP5_Very_Strong

The NM_000422.3(KRT17):c.275A>G(p.Asn92Ser) variant causes a missense change. 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. N92H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT17 NM_000422.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:2
• Conservation: PhyloP100: 6.27

Genes affected

KRT17 (HGNC:6427): (keratin 17) This gene encodes the type I intermediate filament chain keratin 17, expressed in nail bed, hair follicle, sebaceous glands, and other epidermal appendages. Mutations in this gene lead to Jackson-Lawler type pachyonychia congenita and steatocystoma multiplex. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000422.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-41624236-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 14586.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783
• PP5: Variant 17-41624235-T-C is Pathogenic according to our data. Variant chr17-41624235-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 14587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41624235-T-C is described in Lovd as [Likely_pathogenic]. Variant chr17-41624235-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT17	NM_000422.3	c.275A>G	p.Asn92Ser	missense_variant	1/8	ENST00000311208.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT17	ENST00000311208.13	c.275A>G	p.Asn92Ser	missense_variant	1/8	1	NM_000422.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1460480 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726550

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pachyonychia congenita 2 Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1998	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 12, 2022	- -

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 05, 2021	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 14587). This missense change has been observed in individuals with pachyonychia congenita (PMID: 22336949, 31823354). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 92 of the KRT17 protein (p.Asn92Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2016	The N92S missense variant in the KRT17 gene has been reported previously in association with pachyonychia congenita (Smith et al., 1997; Covello et al., 1998; Ofaiche et al., 2014). N92S is the most common hot spot pathogenic variant in the KRT17 gene associated with pachyonychia congenita or steatocystoma multiplex (Human Intermediate Filament Database). The variant 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. This substitution occurs within a known mutational hotspot region (helix initiation motif) that is highly conserved across all species and among all members of the keratin family. Many other pathogenic variants in patients with pachyonychia congenita have been reported in the same residue (N92H/D) and in nearby residues (M88T/R, L91P, R94C/S/G/P/H, L95Q/P) according to the Human Gene Mutation Database (Stenson et al., 2014). It is well established that keratin gene mutations affecting the residues at the ends of the central rod domains of the keratin proteins (helix initiation and termination motifs) interfere with proper keratin intermediate filament assembly and function, resulting in hyperkeratosis (Chamcheu et al., 2011). Therefore, we consider N92S to be pathogenic. -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Steatocystoma multiplex;C1721007:Pachyonychia congenita 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 23, 2021

- -

Abnormality of the skin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0059	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.20	T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.78	D
MutationTaster	Benign	1.0	A;A
Sift4G	Benign	0.25	T
Vest4		0.71
MVP		0.85
ClinPred		1.0	D
GERP RS		5.0

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

Other links and lift over

dbSNP: rs59151893; hg19: chr17-39780487;