NM_000422.3:c.1182-8dupT

Variant names:

• chr17-41620565-G-GA
• rs528557416
• NM_000422.3:c.1182-8dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000422.3(KRT17):​c.1182-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 145,326 control chromosomes in the GnomAD database, including 28 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (28 hom., cov: 31)
  • Exomes 𝑓: 0.085 (45 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT17 NM_000422.3 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.262
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• pachyonychia congenita 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• pachyonychia congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289252 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 17-41620565-G-GA is Benign according to our data. Variant chr17-41620565-G-GA is described in ClinVar as Benign. ClinVar VariationId is 1528628.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0147 (2140/145326) while in subpopulation NFE AF = 0.0195 (1281/65662). AF 95% confidence interval is 0.0186. There are 28 homozygotes in GnomAd4. There are 961 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2140 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.1182-8dupT		splice_region intron	N/A	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.1182-8_1182-7insT		splice_region intron	N/A	ENSP00000308452.8	Q04695
	KRT17	ENST00000862596.1		c.1179-8_1179-7insT		splice_region intron	N/A	ENSP00000532655.1
	KRT17	ENST00000648859.1		c.171-8_171-7insT		splice_region intron	N/A	ENSP00000497161.1	A0A3B3IS58

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2139 AN: 145248 Hom.: 28 Cov.: 31

Gnomad AFR AF: 0.00618

Gnomad AMI AF: 0.0391

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.0533

Gnomad EAS AF: 0.00120

Gnomad SAS AF: 0.00612

Gnomad FIN AF: 0.00559

Gnomad MID AF: 0.0367

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0218

GnomAD2 exomes AF: 0.0719 AC: 6936 AN: 96496 AF XY: 0.0754

Gnomad AFR exome AF: 0.0285

Gnomad AMR exome AF: 0.0747

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.0352

Gnomad FIN exome AF: 0.0336

Gnomad NFE exome AF: 0.0817

Gnomad OTH exome AF: 0.0821

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.0852 AC: 62484 AN: 732962 Hom.: 45 Cov.: 36 AF XY: 0.0839 AC XY: 30025 AN XY: 357924

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0439 AC: 854 AN: 19446

American (AMR) AF: 0.0633 AC: 1232 AN: 19472

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 1551 AN: 11722

East Asian (EAS) AF: 0.0366 AC: 584 AN: 15976

South Asian (SAS) AF: 0.0540 AC: 1857 AN: 34386

European-Finnish (FIN) AF: 0.0349 AC: 872 AN: 24996

Middle Eastern (MID) AF: 0.0832 AC: 165 AN: 1984

European-Non Finnish (NFE) AF: 0.0918 AC: 52850 AN: 575714

Other (OTH) AF: 0.0861 AC: 2519 AN: 29266

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0147 AC: 2140 AN: 145326 Hom.: 28 Cov.: 31 AF XY: 0.0136 AC XY: 961 AN XY: 70470

African (AFR) AF: 0.00616 AC: 246 AN: 39938

American (AMR) AF: 0.0176 AC: 258 AN: 14672

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 181 AN: 3394

East Asian (EAS) AF: 0.00120 AC: 6 AN: 4998

South Asian (SAS) AF: 0.00657 AC: 30 AN: 4564

European-Finnish (FIN) AF: 0.00559 AC: 50 AN: 8944

Middle Eastern (MID) AF: 0.0365 AC: 10 AN: 274

European-Non Finnish (NFE) AF: 0.0195 AC: 1281 AN: 65662

Other (OTH) AF: 0.0217 AC: 43 AN: 1986

Alfa AF: 0.0954 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs528557416; hg19: chr17-39776817;