KLHL24

kelch like family member 24, the group of BTB domain containing|Kelch like

Basic information

Region (hg38): 3:183635610-183684519

Links

ENSG00000114796 ∙ NCBI:54800 ∙ OMIM:611295 ∙ HGNC:25947 ∙ Uniprot:Q6TFL4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• epidermolysis bullosa simplex 6, generalized, with scarring and hair loss (Strong), mode of inheritance: AD
• epidermolysis bullosa simplex 6, generalized, with scarring and hair loss (Moderate), mode of inheritance: AD
• epidermolysis bullosa simplex 6, generalized, with scarring and hair loss (Strong), mode of inheritance: AD
• epidermolysis bullosa simplex 6, generalized, with scarring and hair loss (Supportive), mode of inheritance: AD
• epidermolysis bullosa simplex 6, generalized, with scarring and hair loss (Strong), mode of inheritance: AD
• cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies (Strong), mode of inheritance: AR
• cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies (Limited), mode of inheritance: AR
• hypertrophic cardiomyopathy (Moderate), mode of inheritance: AR
• epidermolysis bullosa simplex 6, generalized, with scarring and hair loss (Moderate), mode of inheritance: AD
• epidermolysis bullosa simplex 6, generalized, with scarring and hair loss (Strong), mode of inheritance: AD
• cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies	AD/AR	Cardiovascular	The condition can involve severe, early-onset cardiomyopathy, and awareness may allow early interventions and management; heart transplant has been described	Cardiovascular; Dermatologic	27798626; 27889062; 29779254; 30226531; 30579426; 30715372; 31649980

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KLHL24 gene.

• Inborn_genetic_diseases (47 variants)
• not_provided (26 variants)
• Epidermolysis_bullosa_simplex_6,_generalized,_with_scarring_and_hair_loss (11 variants)
• KLHL24-related_disorder (8 variants)
• Cardiomyopathy,_familial_hypertrophic,_29,_with_polyglucosan_bodies (6 variants)
• Epidermolysis_bullosa_simplex,_Koebner_type (4 variants)
• Hypertrophic_cardiomyopathy (3 variants)
• Cardiomyopathy (1 variants)
• not_specified (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KLHL24 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000017644.3. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				9	3	12
missense	1	1	56	3	1	62
nonsense	1	1	1			3
start loss	6					6
frameshift		1	1			2
splice donor/acceptor (+/-2bp)						0
Total	8	3	58	12	4

Highest pathogenic variant AF is 0.00000617438

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KLHL24	protein_coding	protein_coding	ENST00000454652	6	48910

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00167	0.997	125732	0	16	125748	0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.88	190	340	0.560	0.0000187	3939
Missense in Polyphen		46	120.69	0.38114		1414
Synonymous	0.0537	117	118	0.994	0.00000623	1157
Loss of Function	2.86	9	24.2	0.373	0.00000134	306

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000251	0.000243
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000616	0.0000615
Middle Eastern	0.00	0.00
South Asian	0.0000982	0.0000980
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Necessary to maintain the balance between intermediate filament stability and degradation, a process that is essential for skin integrity (PubMed:27889062). As part of the BCR(KLHL24) E3 ubiquitin ligase complex, mediates ubiquitination of KRT14 and controls its levels during keratinocytes differentiation (PubMed:27798626). Specifically reduces kainate receptor-mediated currents in hippocampal neurons, most probably by modulating channel properties (By similarity). {ECO:0000250|UniProtKB:Q56A24, ECO:0000269|PubMed:27798626, ECO:0000269|PubMed:27889062}.
• Disease: DISEASE: Epidermolysis bullosa simplex, generalized, with scarring and hair loss (EBSSH) [MIM:617294]: A form of epidermolysis bullosa, a group of mechano-bullous disorders characterized by structural skin fragility, recurrent blister formation and erosion of the skin and mucous membranes occurring spontaneously or after mild trauma. Epidermolysis bullosa simplex is characterized by intraepidermal tissue separation that occurs within the basal keratinocytes at the bottom layer of epidermis. EBSSH is an autosomal dominant epidermolysis bullosa simplex, presenting at birth with extensive skin defects on the extremities, leaving behind hypopigmentation and atrophy with a whirled pattern. Cutaneous fragility and generalized blistering persist during childhood and decrease in adulthood. Adult patients have dyspigmentation and atrophy of the skin, scars, follicular atrophoderma, sparse body hair, progressive diffuse alopecia of the scalp, diffuse palmoplantar keratoderma, and nail changes. {ECO:0000269|PubMed:27798626, ECO:0000269|PubMed:27889062}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gain-of-function mutations that lead to excessive ubiquitination and degradation of KRT14 result in compromised mechanical integrity of basal keratinocytes. Under this pathological condition, trivial mechanical stress can induce blister formation at the basal layer of skin. {ECO:0000269|PubMed:27798626}.

Recessive Scores

• pRec: 0.113

Intolerance Scores

• loftool: 0.391
• rvis_EVS: -0.78
• rvis_percentile_EVS: 12.77

Haploinsufficiency Scores

• pHI: 0.214
• hipred: Y
• hipred_score: 0.822
• ghis: 0.613

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.578

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Klhl24

Gene ontology

• Biological process: protein ubiquitination;intermediate filament organization;protein autoubiquitination;regulation of kainate selective glutamate receptor activity
• Cellular component: cytoplasm;adherens junction;desmosome;axon;Cul3-RING ubiquitin ligase complex;perikaryon
• Molecular function: protein binding