KMT2B

protein-coding

lysine methyltransferase 2B, the group of PHD finger proteins|SET domain containing|Zinc fingers CXXC-type|Lysine methyltransferases

Gene summary

This gene encodes a protein which contains multiple domains including a CXXC zinc finger, three PHD zinc fingers, two FY-rich domains, and a SET (suppressor of variegation, enhancer of zeste, and trithorax) domain. The SET domain is a conserved C-terminal domain that characterizes proteins of the MLL (mixed-lineage leukemia) family. This gene is ubiquitously expressed in adult tissues. It is also amplified in solid tumor cell lines, and may be involved in human cancer. Two alternatively spliced transcript variants encoding distinct isoforms have been reported for this gene, however, the full length nature of the shorter transcript is not known. [provided by RefSeq, Jul 2008]

MANE transcript

NM_014727.3

Inheritance

ClinVar variants

P:170U:1043B:1146

Top phenotype

Dystonia 28, childhood-onset; Intellectual developmental disorder, autosomal dominant 68

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chr19:35,717,973-35,738,880

External References & Databases

Ensembl (ENSG00000272333)

Transcript & Mutation Effects

hg38 • Region Span ~20.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

dystonia 28, childhood-onsetSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015004

Submitter: G2P

dystonia 28, childhood-onsetSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015004

Submitter: PanelApp Australia

dystonia 28, childhood-onsetSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015004

Submitter: Genomics England PanelApp

intellectual developmental disorder, autosomal dominant 68LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030969

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorder with motor featuresDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100516

Submitter: ClinGen

*KMT2B* was first reported in relation to Dystonia 28, childhood-onset and autosomal dominant intellectual developmental disorder in 2018 (Faundes et al., PMID: 29276005). Probands with dystonia have variable presentations and do not all present with intellectual disability. Additionally, some probands with intellectual disability and no dystonia phenotype share their variant with family members who present with dystonia but mild or no intellectual disability.Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. However, the phenotypic differences were determined to be a spectrum of disease rather than two distinct entities. Therefore, the following disease entities, Dystonia 28, childhood-onset and intellectual developmental disorder, autosomal dominant 68, have been lumped into one disease entity, complex neurodevelopmental disorder with motor features. Ten variants (missense, nonsense, and frameshift) that have been reported in 10 probands in 2 publications (PMIDs: 29276005, 33150406) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.The mechanism of pathogenicity is reported to be LOF. This gene-disease relationship is also supported by a non-human animal model (PMID: 23426673). Mice lacking *KMT2B* gene in adult forebrain excitatory neurons display impaired hippocampus-dependent memory function. In summary, there is definitive evidence to support the relationship between *KMT2B* and autosomal dominant complex neurodevelopmental disorder with motor features. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on April 17, 2023 (SOP 9).

dystonia 28, childhood-onsetSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015004

Submitter: Labcorp Genetics (formerly Invitae)

dystonia 28, childhood-onsetSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015004

Submitter: Orphanet

dystonia 28, childhood-onsetDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015004

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Dystonia 28, childhood-onset; Intellectual developmental disorder, autosomal dominant 68AD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: 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

Comments: In Dystonia 28, surgical treatment (with deep brain stimulation) has been reported as effective

Refs: 27839873; 27992417; 29276005; 33150406

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KMT2B variants in ClinVar

25 Conditions Cataloged

not providedTotal: 2334

Inborn genetic diseasesTotal: 444

not specifiedTotal: 185

Dystonia 28, childhood-onsetTotal: 137

KMT2B-related disorderTotal: 119

Intellectual developmental disorder, autosomal dominant 68Total: 55

Intellectual disabilityTotal: 12

See casesTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014727.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	11 clinvar	509 clinvar	133 clinvar	654
missense	1 clinvar	38 clinvar	1008 clinvar	424 clinvar	78 clinvar	1549
nonsense	15 clinvar	17 clinvar	4 clinvar			36
start loss				1 clinvar		1
frameshift	63 clinvar	25 clinvar	2 clinvar			90
splice donor/acceptor (+/-2bp)	4 clinvar	6 clinvar	18 clinvar		1 clinvar	29
Total	83	87	1043	934	212	2359

Highest pathogenic variant AF is 0.000009313291

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014727.3	RefSeq	NP_055542.1	37	MANE Select
ENST00000420124.4	Ensembl	ENSP00000398837.2	37	MANE Select
ENST00000673918.2	Ensembl	ENSP00000501283.1	37	Standard
ENST00000673946.1	Ensembl	ENSP00000501076.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysine degradation - Homo sapiens (human)
Histone Modifications
Gene expression (Transcription)
Generic Transcription Pathway
PKMTs methylate histone lysines

Biological Process

ovarian follicle development
regulation of transcription by RNA polymerase II
memory
oocyte differentiation
gene silencing

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity
protein binding
zinc ion binding

Cellular Component

nucleus
nucleoplasm
histone methyltransferase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000222270
Coding exons: 37
Length: 20859
Individuals with no LoFs: 123835
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 123842
p: 0.0000283

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.43	1209	1.59e+3	0.759	0.000106	16961
Missense (PolyPhen)		322	610.29	0.52762		6075
Synonymous	-4.28	776	639	1.22	0.0000426	5927
Loss of Function	9.52	3	111	0.0269	0.00000640	1224

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000029	0.000027	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Histone methyltransferase. Methylates 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. Plays a central role in beta-globin locus transcription regulation by being recruited by NFE2. Plays an important role in controlling bulk H3K4me during oocyte growth and preimplantation development. Required during the transcriptionally active period of oocyte growth for the establishment and/or maintenance of bulk H3K4 trimethylation (H3K4me3), global transcriptional silencing that preceeds resumption of meiosis, oocyte survival and normal zygotic genome activation. {ECO:0000269|PubMed:17707229}.;

Recessive Scores

pRec: 0.105

Intolerance Scores

RVIS EVS: -5.29
RVIS percentile EVS: 0.06

Essentials

Essential (CRISPR): N

Gene Damage Prediction

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