Genetic Variant KRT17:p.Arg406Cys (chr17-41619677-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000422.3(KRT17):c.1216C>T(p.Arg406Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000036 in 1,612,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

KRT17
NM_000422.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.36

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT17	NM_000422.3 link	c.1216C>T	p.Arg406Cys	missense_variant	Exon 8 of 8	ENST00000311208.13	NP_000413.1	Q04695Q14666

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KRT17	ENST00000311208.13 link	c.1216C>T	p.Arg406Cys	missense_variant	Exon 8 of 8	1	NM_000422.3	ENSP00000308452.8	Q04695
KRT17	ENST00000493253.5 link	n.1603C>T		non_coding_transcript_exon_variant	Exon 7 of 7	2
KRT17	ENST00000649249.1 link	n.492C>T		non_coding_transcript_exon_variant	Exon 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

249834

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135126

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000535

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000377

AC:

AN:

1459888

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with KRT17-related conditions. This variant is present in population databases (rs777503614, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 406 of the KRT17 protein (p.Arg406Cys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;D;T

Eigen

Benign

0.098

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.66

.;T;T

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Uncertain

-0.047

MutationAssessor

Uncertain

2.1

M;M;.

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.8

.;D;.

REVEL

Uncertain

0.62

Sift

Benign

0.12

.;T;.

Sift4G

Benign

0.10

.;T;T

Polyphen

0.0030

B;B;.

Vest4

0.82, 0.82

MutPred

0.47

Loss of MoRF binding (P = 0.0047);Loss of MoRF binding (P = 0.0047);.;

MVP

0.87

MPC

0.37

ClinPred

0.59

GERP RS

4.4

Varity_R

0.15

gMVP

0.64

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