rs58730926

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_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. R94P) 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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7U:1O:1

Conservation

PhyloP100: 5.06

Publications

21 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

sebocystomatosis
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
pachyonychia congenita 2
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
pachyonychia congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KRT17 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000422.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain 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-G is described in ClinVar as Pathogenic. ClinVar VariationId is 14594.Status of the report is no_assertion_criteria_provided, 0 stars.

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 VariationId is 14591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000422.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT17	NM_000422.3	MANE Select	c.280C>T	p.Arg94Cys	missense	Exon 1 of 8	NP_000413.1	Q04695

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT17	ENST00000311208.13	TSL:1 MANE Select	c.280C>T	p.Arg94Cys	missense	Exon 1 of 8	ENSP00000308452.8	Q04695
KRT17	ENST00000862596.1		c.280C>T	p.Arg94Cys	missense	Exon 1 of 8	ENSP00000532655.1
KRT17	ENST00000577817.3	TSL:3	c.235C>T	p.Arg79Cys	missense	Exon 1 of 4	ENSP00000467418.1	K7EPJ9

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

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:

AN:

1460480

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726548

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4628

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000768

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Steatocystoma multiplex (3)

Inborn genetic diseases (1)

Pachyonychia congenita 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.0

PhyloP100

5.1

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.86

Sift

Uncertain

0.023

Sift4G

Uncertain

0.010

PromoterAI

-0.014

Neutral

(source)

Varity_R

0.54

gMVP

0.80

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over