17-41620547-T-C

Position:

• chr17-41620547-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000422.3(KRT17):​c.1193A>G​(p.Tyr398Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT17 NM_000422.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12763199).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT17	NM_000422.3	c.1193A>G	p.Tyr398Cys	missense_variant	7/8	ENST00000311208.13	NP_000413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT17	ENST00000311208.13	c.1193A>G	p.Tyr398Cys	missense_variant	7/8	1	NM_000422.3	ENSP00000308452	P1
KRT17	ENST00000648859.1	c.185A>G	p.Tyr62Cys	missense_variant	2/2			ENSP00000497161
KRT17	ENST00000493253.5	n.1580A>G		non_coding_transcript_exon_variant	6/7	2
KRT17	ENST00000649249.1	n.469A>G		non_coding_transcript_exon_variant	3/4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

The c.1193A>G (p.Y398C) alteration is located in exon 7 (coding exon 7) of the KRT17 gene. This alteration results from a A to G substitution at nucleotide position 1193, causing the tyrosine (Y) at amino acid position 398 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	0.0016	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.22	T;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.70	.;T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.14	N;N;.
MutationTaster	Benign	0.98	N;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.47	.;N;.
REVEL	Benign	0.23
Sift	Benign	0.17	.;T;.
Sift4G	Benign	0.17	.;T;T
Polyphen		0.0	B;B;.
Vest4		0.49, 0.47
MutPred		0.45		Gain of methylation at K399 (P = 0.0144);Gain of methylation at K399 (P = 0.0144);.;
MVP		0.82
MPC		0.35
ClinPred		0.30	T
GERP RS		3.4
Varity_R		0.065
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-39776799;