KMT2D

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

Basic information

Region (hg38): 12:49018974-49060794

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 (Supportive), mode of inheritance: AD
• Kabuki syndrome 1 (Definitive), 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
• 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 (3209 variants)
• not provided (1246 variants)
• Kabuki syndrome 1 (669 variants)
• not specified (307 variants)
• Inborn genetic diseases (189 variants)
• KMT2D-related condition (156 variants)
• Kabuki syndrome 1;Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (14 variants)
• Intellectual disability (8 variants)
• See cases (7 variants)
• Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome;Kabuki syndrome 1 (7 variants)
• Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (5 variants)
• Autism spectrum disorder (4 variants)
• Neurodevelopmental disorder (2 variants)
• KMT2D-related disorders (2 variants)
• Seizure;Intellectual disability (2 variants)
• CHARGE association (1 variants)
• Lung cancer (1 variants)
• Multiple myeloma (1 variants)
• Complement component C1s deficiency (1 variants)
• Microcephaly (1 variants)
• Neurodevelopmental delay (1 variants)
• Abnormality of the nervous system (1 variants)
• Smith-Magenis Syndrome-like (1 variants)
• Eccrine porocarcinoma (1 variants)
• Seizure (1 variants)
• Astrocytoma (1 variants)
• Kabuki syndrome 1;Dandy-Walker syndrome (1 variants)
• Cavernous sinus meningioma (1 variants)
• Lymphoma (1 variants)
• Connective tissue nevi;Seizure (1 variants)
• 6 conditions (1 variants)
• Vein of Galen aneurysmal malformation (1 variants)
• Autism spectrum disorder due to AUTS2 deficiency (1 variants)
• Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome (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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			33	734	163	930
missense	17	43	1133	364	390	1947
nonsense	154	44	1	1		200
start loss		1				1
frameshift	288	85				373
inframe indel		2	114	15		131
splice donor/acceptor (+/-2bp)	32	31	2			65
splice region	3	4	40	69	5	121
non coding		2	12	206	66	286
Total	491	208	1295	1320	619

Highest pathogenic variant AF is 0.0000197

Variants in KMT2D

This is a list of pathogenic ClinVar variants found in the KMT2D region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-49019797-TA-T		Kabuki syndrome	Uncertain significance (Jun 14, 2016)
12-49020736-AC-A		Kabuki syndrome	Uncertain significance (Jun 14, 2016)
12-49020739-C-A			Likely benign (Dec 01, 2022)
12-49021483-GC-G		Kabuki syndrome	Uncertain significance (Jun 14, 2016)
12-49021795-C-T		not specified • Kabuki syndrome	Benign/Likely benign (Feb 01, 2024)
12-49021801-A-G		Kabuki syndrome	Likely benign (Jul 19, 2022)
12-49021805-C-T		Inborn genetic diseases	Uncertain significance (Aug 07, 2017)
12-49021813-A-G		Kabuki syndrome	Likely benign (Jan 03, 2024)
12-49021822-G-A		Kabuki syndrome	Likely benign (Nov 13, 2022)
12-49021828-C-T		Kabuki syndrome	Likely benign (Oct 17, 2023)
12-49021840-G-A		Kabuki syndrome	Likely benign (Aug 22, 2023)
12-49021841-T-C		Kabuki syndrome	Uncertain significance (Aug 17, 2021)
12-49021863-C-G		Kabuki syndrome	Uncertain significance (Dec 25, 2023)
12-49021865-T-C		Neurodevelopmental disorder • Kabuki syndrome	Conflicting classifications of pathogenicity (Oct 29, 2023)
12-49021867-G-A		Kabuki syndrome	Likely benign (Oct 17, 2023)
12-49021873-C-T			Pathogenic (May 01, 2015)
12-49021873-CTGAA-C		Kabuki syndrome 1	Pathogenic (Aug 12, 2020)
12-49021874-T-C		Kabuki syndrome	Pathogenic (Sep 02, 2022)
12-49021876-A-C		Kabuki syndrome	Conflicting classifications of pathogenicity (Dec 27, 2023)
12-49021876-A-G		Kabuki syndrome	Likely benign (Sep 13, 2022)
12-49021882-G-T		Kabuki syndrome	Likely benign (Feb 08, 2022)
12-49021882-GA-G		Kabuki syndrome	Likely benign (Apr 18, 2023)
12-49021884-A-G		Kabuki syndrome	Likely benign (Jan 14, 2024)
12-49021888-G-A		Kabuki syndrome	Likely benign (Feb 10, 2023)
12-49021935-G-A			Likely benign (Sep 26, 2018)

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
1.00	3.55e-26	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

Haploinsufficiency Scores

• pHI: 0.693
• hipred: Y
• hipred_score: 0.637
• ghis: 0.608

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

Mouse Genome Informatics

• Gene name: Kmt2d
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; embryo phenotype; neoplasm; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); skeleton phenotype; immune system phenotype; homeostasis/metabolism phenotype; cellular phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); growth/size/body region phenotype; craniofacial phenotype; muscle phenotype

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