KMT2C

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

Basic information

Region (hg38): 7:152134922-152436644

Previous symbols: [ "MLL3" ]

Links

ENSG00000055609

∙ NCBI:58508 ∙ OMIM:606833 ∙ HGNC:13726 ∙ Uniprot:Q8NEZ4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

Kleefstra syndrome 2 (Moderate), mode of inheritance: AD
Kleefstra syndrome 2 (Strong), mode of inheritance: AD
syndromic intellectual disability (Definitive), mode of inheritance: AD
Kleefstra syndrome 2 (Definitive), mode of inheritance: AD
Kleefstra syndrome 2 (Strong), mode of inheritance: AD
Kleefstra syndrome 2 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Kleefstra syndrome 2	AD	General	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	Craniofacial; Musculoskeletal; Neurologic	22726846; 29069077

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KMT2C gene.

not_provided (1478 variants)
Inborn_genetic_diseases (467 variants)
Kleefstra_syndrome_2 (284 variants)
not_specified (184 variants)
KMT2C-related_disorder (135 variants)
KMT2C-related_NDD (73 variants)
Intellectual_disability (13 variants)
Autism_spectrum_disorder (7 variants)
Tip-toe_gait (7 variants)
See_cases (7 variants)
Syndromic_intellectual_disability (3 variants)
Microcephaly (3 variants)
Neurodevelopmental_disorder (3 variants)
Neurodevelopmental_delay (3 variants)
Multiple_myeloma (2 variants)
Kleefstra_syndrome (1 variants)
Rare_genetic_intellectual_disability (1 variants)
Kleefstra_syndrome_due_to_a_point_mutation (1 variants)
Neurodevelopmental_abnormality (1 variants)
Kleefstra_syndrome_1 (1 variants)
Dystonia,_early-onset,_and/or_spastic_paraplegia (1 variants)
atypical_cerebral_palsy (1 variants)
Developmental_and_epileptic_encephalopathy_92 (1 variants)
Global_developmental_delay (1 variants)
Autism,_susceptiblity_to (1 variants)
Cerebellar_atrophy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KMT2C gene is commonly pathogenic or not. These statistics are base on transcript: NM_000170606.3. 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	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous		2 clinvar	7 clinvar	265 clinvar	81 clinvar	355
missense	1 clinvar	18 clinvar	984 clinvar	422 clinvar	80 clinvar	1505
nonsense	27 clinvar	23 clinvar	11 clinvar	1 clinvar	1 clinvar	63
start loss						0
frameshift	52 clinvar	22 clinvar	7 clinvar			81
splice donor/acceptor (+/-2bp)	5 clinvar	8 clinvar	9 clinvar	3 clinvar	1 clinvar	26
Total	85	73	1018	691	163

Highest pathogenic variant AF is 0.000034696

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KMT2C	protein_coding	protein_coding	ENST00000262189	59	301081

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	3.49e-23	124784	0	964	125748	0.00384

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.14	2226	2.53e+3	0.880	0.000133	31901
Missense in Polyphen		680	1069.8	0.63562		13392
Synonymous	-0.530	919	899	1.02	0.0000474	9586
Loss of Function	12.6	18	219	0.0821	0.0000122	2645

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0102	0.00894
Ashkenazi Jewish	0.00243	0.00218
East Asian	0.00269	0.00229
Finnish	0.00246	0.00222
European (Non-Finnish)	0.00379	0.00331
Middle Eastern	0.00269	0.00229
South Asian	0.0101	0.00840
Other	0.00460	0.00408

dbNSFP

Source: dbNSFP

Function: FUNCTION: Histone methyltransferase. Methylates 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. Central component of the MLL2/3 complex, a coactivator complex of nuclear receptors, involved in transcriptional coactivation. KMT2C/MLL3 may be a catalytic subunit of this complex. May be involved in leukemogenesis and developmental disorder. {ECO:0000269|PubMed:17500065}.;
Disease: DISEASE: Kleefstra syndrome 2 (KLEFS2) [MIM:617768]: A form of Kleefstra syndrome, an autosomal dominant disease characterized by variable mental retardation, psychomotor developmental delay, seizures, behavioral abnormalities, and facial dysmorphisms. {ECO:0000269|PubMed:22726846, ECO:0000269|PubMed:29069077}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Lysine degradation - Homo sapiens (human);Histone Modifications;Pathways Affected in Adenoid Cystic Carcinoma;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;Lysine metabolism;Chromatin organization;Transcriptional regulation by RUNX1 (Consensus)

Recessive Scores

pRec: 0.106

Intolerance Scores

loftool
rvis_EVS: -2.52
rvis_percentile_EVS: 0.91

Haploinsufficiency Scores

pHI: 0.469
hipred: Y
hipred_score: 0.683
ghis: 0.600

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2
essential_gene_gene_trap: H
gene_indispensability_pred
gene_indispensability_score

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Kmt2c
Phenotype: cellular phenotype; growth/size/body region phenotype; vision/eye phenotype; reproductive system phenotype; 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);

Gene ontology

Biological process: regulation of megakaryocyte differentiation;positive regulation of transcription by RNA polymerase II;histone H3-K4 methylation
Cellular component: nucleus;nucleoplasm;histone methyltransferase complex;MLL3/4 complex
Molecular function: DNA binding;transcription coactivator activity;RNA binding;protein binding;transferase activity, transferring acyl groups;histone-lysine N-methyltransferase activity;histone binding;histone methyltransferase activity (H3-K4 specific);metal ion binding