KMT2D

lysine methyltransferase 2D, the group of PHD finger proteins|SET domain containing|Lysine methyltransferases

Basic information

Region (hg38): 12:49018975-49060794

Previous symbols: [ "TNRC21", "MLL2" ]

Links

ENSG00000167548 ∙ NCBI:8085 ∙ OMIM:602113 ∙ HGNC:7133 ∙ Uniprot:O14686 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Kabuki syndrome 1 (Definitive), mode of inheritance: AD
• Kabuki syndrome 1 (Definitive), mode of inheritance: AD
• Kabuki syndrome (Supportive), mode of inheritance: AD
• choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome (Moderate), mode of inheritance: AD
• Kabuki syndrome 1 (Definitive), mode of inheritance: AD
• Kabuki syndrome 1 (Strong), mode of inheritance: AD
• branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (Strong), mode of inheritance: AD
• choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome (Definitive), mode of inheritance: AD
• Kabuki syndrome 1 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome; Kabuki syndrome 1	AD	Audiologic/Otolaryngologic; Cardiovascular; Endocrine; Renal	Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome can include hearing loss, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Individuals have been described with endocrine anomalies including hypothyroidism and growth hormone deficiency, and awareness may allow medical management; In Kabuki syndrome, congenital heart defects, as well as arrhythmias, are frequent in affected individuals, and surveillance may allow early diagnosis and treatment; Individuals may have renal anomalies and/or vesicoureteral reflux, and screening for renal anomalies (eg, with ultrasound and functional testing) may allow measures to help monitor and preserve renal function	Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dental; Endocrine; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic; Renal	3067577; 8048822; 10190924; 11343317; 11665999; 12002156; 15108197; 15887282; 20711175; 21671394; 21607748; 21882399; 22126750; 23535010; 23913813; 29321794; 31949313; 32083401

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KMT2D gene.

• Kabuki_syndrome (5039 variants)
• not_provided (1603 variants)
• Kabuki_syndrome_1 (1462 variants)
• KMT2D-related_disorder (819 variants)
• Choanal_atresia-athelia-hypothyroidism-delayed_puberty-short_stature_syndrome (592 variants)
• Inborn_genetic_diseases (473 variants)
• not_specified (415 variants)
• Intellectual_disability (24 variants)
• See_cases (8 variants)
• Branchial_cleft_anomaly (6 variants)
• Autism_spectrum_disorder (4 variants)
• Microcephaly (3 variants)
• Seizure (2 variants)
• Lung_cancer (2 variants)
• Neurodevelopmental_disorder (2 variants)
• Dystonia,_early-onset,_and/or_spastic_paraplegia (2 variants)
• Lymphoma (2 variants)
• Eccrine_porocarcinoma (1 variants)
• Abnormal_pinna_morphology (1 variants)
• Left_ventricular_noncompaction (1 variants)
• Complement_component_C1s_deficiency (1 variants)
• Multiple_myeloma (1 variants)
• Rare_genetic_intellectual_disability (1 variants)
• Congenital_anomaly_of_kidney_and_urinary_tract (1 variants)
• Stenosis_of_the_external_auditory_canal (1 variants)
• Amblyopia (1 variants)
• Autism_spectrum_disorder_due_to_AUTS2_deficiency (1 variants)
• Choanal_atresia (1 variants)
• Neurodevelopmental_abnormality (1 variants)
• Smith-Magenis_Syndrome-like (1 variants)
• Dandy-Walker_syndrome (1 variants)
• Rubinstein_Taybi_like_syndrome (1 variants)
• Astrocytoma (1 variants)
• CHARGE_syndrome (1 variants)
• Strabismus (1 variants)
• Familial_thoracic_aortic_aneurysm_and_aortic_dissection (1 variants)
• Neurodevelopmental_delay (1 variants)
• Autism (1 variants)
• VISS_syndrome (1 variants)
• Abnormality_of_the_nervous_system (1 variants)
• Connective_tissue_nevi (1 variants)
• Male_infertility_with_spermatogenesis_disorder (1 variants)
• Microtia (1 variants)
• Vein_of_Galen_aneurysmal_malformation (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KMT2D gene is commonly pathogenic or not. These statistics are base on transcript: NM_000003482.4. 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	7	3	49	1275	251	1585
missense	42	93	1984	1068	505	3692
nonsense	220	62	27	1		310
start loss		1				1
frameshift	394	126	11			531
splice donor/acceptor (+/-2bp)	51	44	19	2		116
Total	714	329	2090	2346	756

Highest pathogenic variant AF is 0.000021027565

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KMT2D	protein_coding	protein_coding	ENST00000301067	54	40800

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		124655	0	21	124676	0.0000842

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.73	2541	3.13e+3	0.812	0.000188	35136
Missense in Polyphen		553	854.32	0.6473		9611
Synonymous	-1.43	1365	1.30e+3	1.05	0.0000776	12026
Loss of Function	13.0	15	224	0.0669	0.0000122	2432

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000557	0.000485
Ashkenazi Jewish	0.000201	0.000199
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000448	0.0000442
Middle Eastern	0.00	0.00
South Asian	0.0000656	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Histone methyltransferase. Methylates 'Lys-4' of histone H3 (H3K4me). H3K4me represents a specific tag for epigenetic transcriptional activation. Acts as a coactivator for estrogen receptor by being recruited by ESR1, thereby activating transcription. {ECO:0000269|PubMed:16603732, ECO:0000269|PubMed:17500065, ECO:0000269|PubMed:17851529}.
• Disease: DISEASE: Kabuki syndrome 1 (KABUK1) [MIM:147920]: A congenital mental retardation syndrome with additional features, including postnatal dwarfism, a peculiar facies characterized by long palpebral fissures with eversion of the lateral third of the lower eyelids, a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of the vertebrae, hands, and hip joints, and recurrent otitis media in infancy. {ECO:0000269|PubMed:20711175, ECO:0000269|PubMed:21280141, ECO:0000269|PubMed:21607748, ECO:0000269|PubMed:21658225, ECO:0000269|PubMed:21671394, ECO:0000269|PubMed:22126750, ECO:0000269|PubMed:23320472, ECO:0000269|PubMed:23913813, ECO:0000269|PubMed:24739679}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Cushing,s syndrome - Homo sapiens (human);Lysine degradation - Homo sapiens (human);Histone Modifications;Signaling by WNT;Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;PKMTs methylate histone lysines;RNA Polymerase II Transcription;RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function;Chromatin modifying enzymes;Chromatin organization;Transcriptional regulation by RUNX1;Formation of the beta-catenin:TCF transactivating complex;TCF dependent signaling in response to WNT (Consensus)

Recessive Scores

• pRec: 0.105

Intolerance Scores

• rvis_EVS: -5.29
• rvis_percentile_EVS: 0.06

Essentials

• essential_gene_CRISPR: E
• essential_gene_gene_trap: N

Gene Damage Prediction

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

Zebrafish Information Network

• Gene name: kmt2d
• Affected structure: chondrocyte
• Phenotype tag: abnormal
• Phenotype quality: position

Gene ontology

• Biological process: oocyte growth;chromatin silencing;regulation of transcription, DNA-templated;positive regulation of cell population proliferation;positive regulation of intracellular estrogen receptor signaling pathway;response to estrogen;regulation of megakaryocyte differentiation;positive regulation of transcription by RNA polymerase II;oogenesis;histone H3-K4 methylation;beta-catenin-TCF complex assembly
• Cellular component: nucleus;nucleoplasm;histone methyltransferase complex;MLL3/4 complex
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;DNA binding;transcription coactivator activity;protein binding;histone-lysine N-methyltransferase activity;histone binding;histone methyltransferase activity (H3-K4 specific);transcription regulatory region DNA binding;metal ion binding