rs117941474

Variant names:

• chr17-41619618-C-T
• rs117941474
• NM_000422.3:c.1275G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000422.3(KRT17):​c.1275G>A​(p.Glu425Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0273 in 1,612,184 control chromosomes in the GnomAD database, including 710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (54 hom., cov: 32)
  • Exomes 𝑓: 0.028 (656 hom.)
• Consequence: KRT17 NM_000422.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.13
• Publications: 3 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 17-41619618-C-T is Benign according to our data. Variant chr17-41619618-C-T is described in ClinVar as Benign. ClinVar VariationId is 1599894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0212 (3236/152288) while in subpopulation NFE AF = 0.0305 (2071/68000). AF 95% confidence interval is 0.0294. There are 54 homozygotes in GnomAd4. There are 1536 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3236 AD gene.

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.1275G>A	p.Glu425Glu	synonymous	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.1275G>A	p.Glu425Glu	synonymous	Exon 8 of 8	ENSP00000308452.8	Q04695
	KRT17	ENST00000862596.1		c.1272G>A	p.Glu424Glu	synonymous	Exon 8 of 8	ENSP00000532655.1
	KRT17	ENST00000493253.5	TSL:2	n.1662G>A		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3237 AN: 152170 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00654

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0281

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.0202

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0305

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.0216 AC: 5424 AN: 251130 AF XY: 0.0214

Gnomad AFR exome AF: 0.00480

Gnomad AMR exome AF: 0.0215

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0209

Gnomad NFE exome AF: 0.0307

Gnomad OTH exome AF: 0.0326

GnomAD4 exome AF: 0.0279 AC: 40796 AN: 1459896 Hom.: 656 Cov.: 32 AF XY: 0.0273 AC XY: 19833 AN XY: 726246

African (AFR) AF: 0.00464 AC: 155 AN: 33414

American (AMR) AF: 0.0225 AC: 1007 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0292 AC: 762 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00602 AC: 519 AN: 86172

European-Finnish (FIN) AF: 0.0214 AC: 1140 AN: 53390

Middle Eastern (MID) AF: 0.0239 AC: 99 AN: 4144

European-Non Finnish (NFE) AF: 0.0319 AC: 35437 AN: 1111996

Other (OTH) AF: 0.0278 AC: 1677 AN: 60222

GnomAD4 genome AF: 0.0212 AC: 3236 AN: 152288 Hom.: 54 Cov.: 32 AF XY: 0.0206 AC XY: 1536 AN XY: 74472

African (AFR) AF: 0.00652 AC: 271 AN: 41570

American (AMR) AF: 0.0280 AC: 429 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 107 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00621 AC: 30 AN: 4828

European-Finnish (FIN) AF: 0.0202 AC: 214 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0305 AC: 2071 AN: 68000

Other (OTH) AF: 0.0327 AC: 69 AN: 2112

Alfa AF: 0.0254 Hom.: 29

Bravo AF: 0.0214

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.0320

EpiControl AF: 0.0339

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.59
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs117941474; hg19: chr17-39775870;