NM_005557.4:c.1244_1270delCCACCTACCGCCGCCTGCTGGAGGGCGinsGGC

Variant names:

• chr17-41610341-CGCCCTCCAGCAGGCGGCGGTAGGTGG-GCC
• rs1555573633
• NM_005557.4:c.1244_1270delCCACCTACCGCCGCCTGCTGGAGGGCGinsGGC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM4 PP3 PP5

The NM_005557.4(KRT16):​c.1244_1270delCCACCTACCGCCGCCTGCTGGAGGGCGinsGGC​(p.Ala415_Glu424delinsGlyGln) variant causes a missense, disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT16 NM_005557.4 missense, disruptive_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.26
• Publications: 0 publications found

Genes affected

KRT16 (HGNC:6423): (keratin 16) The protein encoded by this gene is a member of the keratin gene family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins. Most of the type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains and are clustered in a region of chromosome 17q12-q21. This keratin has been coexpressed with keratin 14 in a number of epithelial tissues, including esophagus, tongue, and hair follicles. Mutations in this gene are associated with type 1 pachyonychia congenita, non-epidermolytic palmoplantar keratoderma and unilateral palmoplantar verrucous nevus. [provided by RefSeq, Jul 2008]

KRT16 Gene-Disease associations (from GenCC):

• pachyonychia congenita 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• palmoplantar keratoderma, nonepidermolytic, focal 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• isolated focal non-epidermolytic palmoplantar keratoderma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pachyonychia congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005557.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 17-41610341-CGCCCTCCAGCAGGCGGCGGTAGGTGG-GCC is Pathogenic according to our data. Variant chr17-41610341-CGCCCTCCAGCAGGCGGCGGTAGGTGG-GCC is described in ClinVar as [Pathogenic]. Clinvar id is 14610.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT16	NM_005557.4	c.1244_1270delCCACCTACCGCCGCCTGCTGGAGGGCGinsGGC	p.Ala415_Glu424delinsGlyGln	missense_variant, disruptive_inframe_deletion		ENST00000301653.9	NP_005548.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT16	ENST00000301653.9	c.1244_1270delCCACCTACCGCCGCCTGCTGGAGGGCGinsGGC	p.Ala415_Glu424delinsGlyGln	missense_variant, disruptive_inframe_deletion		1	NM_005557.4	ENSP00000301653.3
KRT16	ENST00000593067.1	c.*42_*68delCCACCTACCGCCGCCTGCTGGAGGGCGinsGGC		downstream_gene_variant		3		ENSP00000467124.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Palmoplantar keratoderma, nonepidermolytic, focal 1 Pathogenic:1

Jun 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

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

Other links and lift over

dbSNP: rs1555573633; hg19: chr17-39766593;