17-41619667-C-A

Variant names:

• chr17-41619667-C-A
• rs754301737
• NM_000422.3:c.1226G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000422.3(KRT17):​c.1226G>T​(p.Arg409Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,898 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRT17 NM_000422.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• pachyonychia congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1226G>T	p.Arg409Leu	missense	Exon 8 of 8	NP_000413.1	Q04695

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT17	ENST00000311208.13	TSL:1 MANE Select	c.1226G>T	p.Arg409Leu	missense	Exon 8 of 8	ENSP00000308452.8	Q04695
	KRT17	ENST00000862596.1		c.1223G>T	p.Arg408Leu	missense	Exon 8 of 8	ENSP00000532655.1
	KRT17	ENST00000493253.5	TSL:2	n.1613G>T		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459898 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726244

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4142

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60222

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	0.023
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.032	D
Polyphen		0.076	B
Vest4		0.76
MutPred		0.57		Loss of MoRF binding (P = 0.0068)
MVP		0.85
MPC		0.36
ClinPred		0.97	D
GERP RS		4.4
Varity_R		0.28
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs754301737; hg19: chr17-39775919;