KRT4

protein-coding

keratin 4, the group of Keratins, type II

Gene summary

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. This type II cytokeratin is specifically expressed in differentiated layers of the mucosal and esophageal epithelia with family member KRT13. Mutations in these genes have been associated with White Sponge Nevus, characterized by oral, esophageal, and anal leukoplakia. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Jul 2008]

Previous symbols:

CYK4

MANE transcript

NM_002272.4

Inheritance

ClinVar variants

P:1U:109B:58

Top phenotype

White sponge nevus 1

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr12:52,806,549-52,814,116

External References & Databases

Ensembl (ENSG00000170477)

Transcript & Mutation Effects

hg38 • Region Span ~7.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

white sponge nevus 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008676

Submitter: PanelApp Australia

hereditary mucosal leukokeratosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015748

Submitter: Orphanet

white sponge nevus 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008676

Submitter: Labcorp Genetics (formerly Invitae)

white sponge nevus 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008676

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

White sponge nevus 1AD

Manifestation: Dermatologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 7493030; 10652003; 12828738

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KRT4 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 119

White sponge nevus 1Total: 66

not providedTotal: 17

not specifiedTotal: 11

KRT4-related disorderTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002272.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	18 clinvar	7 clinvar	29
missense	1 clinvar		103 clinvar	27 clinvar	4 clinvar	135
nonsense				1 clinvar		1
start loss						0
frameshift				1 clinvar		1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	0	109	47	11	168

Highest pathogenic variant AF is 0.0000030978129

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002272.4	RefSeq	NP_002263.3	9	MANE Select
ENST00000551956.2	Ensembl	ENSP00000448220.1	9	MANE Select
ENST00000548097.5	Ensembl	ENSP00000449755.1	2	Standard
ENST00000552668.1	Ensembl	ENSP00000447320.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Keratinization
Developmental Biology

Biological Process

cytoskeleton organization
epithelial cell differentiation
keratinization
negative regulation of epithelial cell proliferation
cornification

Molecular Function

structural molecule activity
protein binding

Cellular Component

nucleus
cytosol
intermediate filament
cell surface
keratin filament

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000551956
Coding exons: 9
Length: 8003
Individuals with no LoFs: 125548
Homozygous LoFs: 0
Heterozygous LoFs: 200
Defined: 125748
p: 0.000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.456	314	292	1.08	0.0000180	3414
Missense (PolyPhen)		114	108.35	1.0521		1341
Synonymous	-1.10	135	120	1.13	0.00000783	1019
Loss of Function	1.33	18	25.2	0.715	0.00000157	262

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00094	0.00092	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00030	0.00029	rare
South Asian	0.0044	0.0044	notable
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: White sponge nevus 1 (WSN1) [MIM:193900]: A rare disorder characterized by the presence of soft, white, and spongy plaques in the oral mucosa. The characteristic histopathologic features are epithelial thickening, parakeratosis, and vacuolization of the suprabasal layer of oral epithelial keratinocytes. Less frequently the mucous membranes of the nose, esophagus, genitalia and rectum are involved. {ECO:0000269|PubMed:10652003, ECO:0000269|PubMed:12828738}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.219

Intolerance Scores

LoFtool: 0.261
RVIS EVS: 0.34
RVIS percentile EVS: 73.68

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.643

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium