rs58730926

Positions:

• chr17-41624230-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000422.3(KRT17):​c.280C>T​(p.Arg94Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,612,620 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R94H) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRT17 NM_000422.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1 O:1
• Conservation: PhyloP100: 5.06

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]

KRT17 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a region_of_interest Coil 1A (size 36) in uniprot entity K1C17_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000422.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-41624229-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-41624230-G-A is Pathogenic according to our data. Variant chr17-41624230-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41624230-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT17	NM_000422.3	c.280C>T	p.Arg94Cys	missense_variant	1/8	ENST00000311208.13	NP_000413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT17	ENST00000311208.13	c.280C>T	p.Arg94Cys	missense_variant	1/8	1	NM_000422.3	ENSP00000308452.8

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460480 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726548

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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 AF: 0.0000131 AC: 2 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 19, 2022	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: 14591). This missense change has been observed in individuals with pachyonychia congenita and/or steatocystoma multiplex (PMID: 9767294, 25946540, 26165312, 29218738, 31823354). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs58730926, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 94 of the KRT17 protein (p.Arg94Cys). -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2022	Located within the helix initiation in 1A domain that is intolerant of change; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22336949, 31823354, 9767294, 29218738, 26165312, 25946540) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -

Steatocystoma multiplex Pathogenic:2 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Feb 04, 2022	This sequence change in KRT17 is predicted to replace arginine with cysteine at codon 94, p.(Arg94Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the intermediate filament rod domain, a region (amino acids 92 - 95) that is a mutational hotspot (ClinVar). There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in gnomAD v3.1 is 0.02% (1/5,170 alleles) in the East Asian population, and another singleton is present in the African/African-American population (1/41,428 alleles). This variant has been reported in at least six probands with pachyonychia congenita or steatocystoma multiplex, and segregates with disease in multiple families (PMID: 9767294, 11809119, 22336949, 26165312). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS4_Moderate, PM1, PM2_Supporting, PP3. -
Uncertain significance, flagged submission	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

Pachyonychia congenita 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	.;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.0	M;M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.8	.;D;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.023	.;D;.
Sift4G	Uncertain	0.010	.;D;.
Polyphen		0.32	B;B;.
Vest4		0.99
MutPred		0.99		Gain of catalytic residue at L95 (P = 0.0193);Gain of catalytic residue at L95 (P = 0.0193);.;
MVP		0.96
MPC		0.68
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.54
gMVP		0.80

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: rs58730926; hg19: chr17-39780482; COSMIC: COSV60861109; COSMIC: COSV60861109;