Variant 17-41620683-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000422.3(KRT17):c.1157G>A(p.Arg386His) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,832 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

KRT17
NM_000422.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.16

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT17	NM_000422.3 linkuse as main transcript	c.1157G>A	p.Arg386His	missense_variant	6/8	ENST00000311208.13	NP_000413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
KRT17	ENST00000311208.13 linkuse as main transcript	c.1157G>A	p.Arg386His	missense_variant	6/8	1	NM_000422.3	ENSP00000308452	P1
KRT17	ENST00000648859.1 linkuse as main transcript	c.149G>A	p.Arg50His	missense_variant	1/2			ENSP00000497161
KRT17	ENST00000493253.5 linkuse as main transcript	n.1544G>A		non_coding_transcript_exon_variant	5/7	2
KRT17	ENST00000649249.1 linkuse as main transcript	n.433G>A		non_coding_transcript_exon_variant	2/4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459832

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726224

show subpopulations

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 19, 2023

ClinVar contains an entry for this variant (Variation ID: 1995323). This variant has not been reported in the literature in individuals affected with KRT17-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 386 of the KRT17 protein (p.Arg386His). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 KRT17 protein function. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;D;D

Eigen

Benign

0.12

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.16

.;T;T

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.79

D;D;D

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.5

M;M;.

MutationTaster

Benign

0.82

D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.1

.;N;.

REVEL

Pathogenic

0.67

Sift

Benign

0.083

.;T;.

Sift4G

Uncertain

0.043

.;D;T

Polyphen

0.13

B;B;.

Vest4

0.63, 0.57

MutPred

0.61

Loss of stability (P = 0.0432);Loss of stability (P = 0.0432);.;

MVP

0.95

MPC

0.38

ClinPred

0.98

GERP RS

3.8

Varity_R

0.21

gMVP

0.56

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over