KMT2C

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

Basic information

Region (hg38): 7:152134921-152436644

Previous symbols: [ "MLL3" ]

Links

ENSG00000055609 ∙ NCBI:58508 ∙ OMIM:606833 ∙ HGNC:13726 ∙ Uniprot:Q8NEZ4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• intellectual disability, autosomal dominant 40 (Strong), mode of inheritance: AD
• Kleefstra syndrome 2 (Moderate), mode of inheritance: AD
• Kleefstra syndrome 2 (Strong), mode of inheritance: AD
• syndromic intellectual disability (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 (968 variants)
• Kleefstra syndrome 2 (183 variants)
• Inborn genetic diseases (148 variants)
• not specified (118 variants)
• KMT2C-related condition (27 variants)
• Autism spectrum disorder (7 variants)
• Intellectual disability (7 variants)
• See cases (5 variants)
• Tip-toe gait (4 variants)
• KMT2C-related disorders (3 variants)
• Neurodevelopmental disorder (3 variants)
• Neurodevelopmental delay (3 variants)
• Autistic behavior (2 variants)
• Kleefstra syndrome 1 (1 variants)
• atypical cerebral palsy (1 variants)
• Autism, susceptiblity to (1 variants)
• Neurodevelopmental abnormality (1 variants)
• Autism;Intellectual disability (1 variants)
• Epileptic encephalopathy, infantile or early childhood, 2 (1 variants)
• Microcephaly (1 variants)
• Kleefstra syndrome due to a point mutation (1 variants)
• Cerebellar atrophy;Global developmental delay;Kleefstra syndrome 2 (1 variants)
• Global developmental delay;Seizure (1 variants)
• Intellectual disability;Autistic behavior (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.

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			3	159	69	231
missense		7	504	179	84	774
nonsense	12	9	4		3	28
start loss						0
frameshift	22	12	2			36
inframe indel			9	1		10
splice donor/acceptor (+/-2bp)	4	5	4	2	1	16
splice region	1		14	39	18	72
non coding				61	25	86
Total	38	33	526	402	182

Variants in KMT2C

This is a list of pathogenic ClinVar variants found in the KMT2C region.

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

Position	Type	Phenotype	Significance	ClinVar
7-152136861-C-A		Autism spectrum disorder	Likely benign (-)
7-152136899-A-T		Kleefstra syndrome 2	Uncertain significance (Oct 05, 2022)
7-152136909-T-G			Benign (May 11, 2023)
7-152136917-T-C			Uncertain significance (Jun 26, 2019)
7-152136932-C-T			Likely benign (May 01, 2023)
7-152136934-G-A			Likely benign (Dec 12, 2023)
7-152138860-A-G			Likely benign (Jun 20, 2022)
7-152138869-G-A			Likely benign (Dec 27, 2022)
7-152138874-A-G			Likely benign (Dec 02, 2021)
7-152138879-T-C			Uncertain significance (Dec 06, 2019)
7-152138887-C-T			Uncertain significance (Mar 10, 2022)
7-152138889-C-T			Likely benign (Jan 01, 2024)
7-152138896-T-C		KMT2C-related disorder	Uncertain significance (Dec 19, 2022)
7-152138902-T-C		Kleefstra syndrome 2	Uncertain significance (Sep 20, 2022)
7-152138908-C-T			Likely benign (Jun 22, 2023)
7-152138915-C-T			Benign (Dec 11, 2023)
7-152139169-G-A			Likely benign (Mar 25, 2023)
7-152139171-T-A		not specified	Likely benign (Mar 19, 2024)
7-152139172-C-G			Likely benign (Dec 27, 2021)
7-152139175-C-A			Likely benign (Dec 27, 2021)
7-152139179-G-A			Likely benign (Jul 17, 2023)
7-152139212-G-A			Benign (Jul 17, 2023)
7-152139226-C-T			Uncertain significance (Jun 19, 2022)
7-152139237-C-T		Inborn genetic diseases	Uncertain significance (Jul 08, 2022)
7-152139255-C-T			Likely benign (May 05, 2022)

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

• 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_gene_trap: H

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