rs58181827

Variant names:

• chr17-41612297-TAGG-T
• rs58181827
• NM_005557.4:c.389_391delCCT

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The NM_005557.4(KRT16):​c.389_391delCCT​(p.Ser130del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT16 NM_005557.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.20

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a region_of_interest Coil 1A (size 35) in uniprot entity K1C16_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_005557.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_005557.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-41612297-TAGG-T is Pathogenic according to our data. Variant chr17-41612297-TAGG-T is described in ClinVar as [Pathogenic]. Clinvar id is 14603.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-41612297-TAGG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT16	NM_005557.4	c.389_391delCCT	p.Ser130del	disruptive_inframe_deletion	Exon 1 of 8	ENST00000301653.9	NP_005548.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT16	ENST00000301653.9	c.389_391delCCT	p.Ser130del	disruptive_inframe_deletion	Exon 1 of 8	1	NM_005557.4	ENSP00000301653.3
KRT16	ENST00000593067.1	c.-312-14_-312-12delCCT		intron_variant	Intron 1 of 6	3		ENSP00000467124.1
KRT16	ENST00000588319.1	n.466_468delCCT		non_coding_transcript_exon_variant	Exon 1 of 1	6
KRT16	ENST00000590990.1	c.*243_*245delCCT		downstream_gene_variant		4		ENSP00000467105.1

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:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 14, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.389_391delCCT pathogenic variant in the KRT16 gene results in an in-frame deletion of a single Serine residue. The deletion has been previously published in association with pachyonychia congenita type 1 (Smith et al., 1999). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these population. The deleted Serine residue is located at a position within the Coil1A region of the KRT16 protein that is a hotpot for pathogenic variants. -

Pachyonychia congenita 1 Pathogenic:1

Oct 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs58181827; hg19: chr17-39768549;