17-41619622-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000422.3(KRT17):c.1271G>A(p.Arg424His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,612,166 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R424C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: KRT17 NM_000422.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.907

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030026138).
• BP6: Variant 17-41619622-C-T is Benign according to our data. Variant chr17-41619622-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 728538.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT17	NM_000422.3	c.1271G>A	p.Arg424His	missense_variant	8/8	ENST00000311208.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT17	ENST00000311208.13	c.1271G>A	p.Arg424His	missense_variant	8/8	1	NM_000422.3	P1
KRT17	ENST00000493253.5	n.1658G>A		non_coding_transcript_exon_variant	7/7	2
KRT17	ENST00000649249.1	n.547G>A		non_coding_transcript_exon_variant	4/4

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251090 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135726

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000171 AC: 250 AN: 1459894 Hom.: 0 Cov.: 32 AF XY: 0.000160 AC XY: 116 AN XY: 726246

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74460

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000215 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.25	N
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.030	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.44	N;N;.
MutationTaster	Benign	1.0	N;D
PrimateAI	Benign	0.37	T
Polyphen		0.0030	B;B;.
Vest4		0.35, 0.38
MVP		0.82
MPC		0.34
ClinPred		0.059	T
GERP RS		3.5
Varity_R		0.075
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs148013099; hg19: chr17-39775874; COSMIC: COSV60861236; COSMIC: COSV60861236;