rs267607459

Positions:

• chr12-52492670-CTTG-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_005554.4(KRT6A):​c.516_518del​(p.Asn172del) variant causes a inframe deletion change. 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: KRT6A NM_005554.4 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:2
• Conservation: PhyloP100: 6.47

Genes affected

KRT6A (HGNC:6443): (keratin 6A) The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. As many as six of this type II cytokeratin (KRT6) have been identified; the multiplicity of the genes is attributed to successive gene duplication events. The genes are expressed with family members KRT16 and/or KRT17 in the filiform papillae of the tongue, the stratified epithelial lining of oral mucosa and esophagus, the outer root sheath of hair follicles, and the glandular epithelia. This KRT6 gene in particular encodes the most abundant isoform. Mutations in these genes have been associated with pachyonychia congenita. In addition, peptides from the C-terminal region of the protein have antimicrobial activity against bacterial pathogens. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_005554.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_005554.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 12-52492670-CTTG-C is Pathogenic according to our data. Variant chr12-52492670-CTTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 14634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-52492670-CTTG-C is described in Lovd as [Pathogenic]. Variant chr12-52492670-CTTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT6A	NM_005554.4	c.516_518del	p.Asn172del	inframe_deletion	1/9	ENST00000330722.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT6A	ENST00000330722.7	c.516_518del	p.Asn172del	inframe_deletion	1/9	1	NM_005554.4	P1
KRT6A	ENST00000549898.5	n.37_39del		non_coding_transcript_exon_variant	1/5	3

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:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pachyonychia congenita 3 Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 20, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2005	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2020	In-frame deletion of one amino acid within the highly conserved helix initiation motif at the beginning of the 1A segment of the rod domain, which is a known mutation hotspot; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Lost residue N172 is located with the helix initiation motif in the 1A domain that is intolerant to change; This variant is associated with the following publications: (PMID: 27183391, 10232401, 11886499, 7545493, 21554383, 21326300, 19416275, 24611874, 21576551, 28411774, 31777952, 31823354) -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs606231214; hg19: chr12-52886454;