SETD2

SET domain containing 2, histone lysine methyltransferase, the group of SET domain containing|Lysine methyltransferases

Basic information

Region (hg38): 3:47016427-47164113

Links

ENSG00000181555 ∙ NCBI:29072 ∙ OMIM:612778 ∙ HGNC:18420 ∙ Uniprot:Q9BYW2 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Sotos syndrome (Supportive), mode of inheritance: AD
• Luscan-Lumish syndrome (Strong), mode of inheritance: AD
• Rabin-Pappas syndrome (Strong), mode of inheritance: AD
• SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome (Strong), mode of inheritance: AD
• SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Luscan-Lumish syndrome	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	22495309; 23160955; 24852293; 25363768; 26084711

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SETD2 gene.

• Luscan-Lumish syndrome (684 variants)
• not provided (310 variants)
• not specified (78 variants)
• Inborn genetic diseases (78 variants)
• SETD2-related condition (16 variants)
• Autism spectrum disorder (5 variants)
• Rabin-Pappas syndrome;Intellectual developmental disorder, autosomal dominant 70;Luscan-Lumish syndrome (3 variants)
• See cases (3 variants)
• Intellectual developmental disorder, autosomal dominant 70 (2 variants)
• Acute megakaryoblastic leukemia without down syndrome (2 variants)
• Neurodevelopmental disorder (2 variants)
• Intellectual developmental disorder, autosomal dominant 70;Luscan-Lumish syndrome;Rabin-Pappas syndrome (2 variants)
• Luscan-Lumish syndrome;Rabin-Pappas syndrome;Intellectual developmental disorder, autosomal dominant 70 (1 variants)
• SETD2-related disorder (1 variants)
• Congenital cerebellar hypoplasia (1 variants)
• Rabin-Pappas syndrome (1 variants)
• Autism;Intellectual disability (1 variants)
• Seizure;Intellectual disability;Autistic behavior (1 variants)
• Intellectual disability (1 variants)
• Autistic behavior (1 variants)
• Cerebellar vermis hypoplasia;Corpus callosum, agenesis of;Luscan-Lumish syndrome (1 variants)
• Seizure (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SETD2 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			8	184	14	206
missense	2	3	450	87	51	593
nonsense	11	3				14
start loss			1	1		2
frameshift	10	5	2			17
inframe indel			8	3		11
splice donor/acceptor (+/-2bp)	1	2				3
splice region			7	11	1	19
non coding			2	50	41	93
Total	24	13	471	325	106

Highest pathogenic variant AF is 0.00000657

Variants in SETD2

This is a list of pathogenic ClinVar variants found in the SETD2 region.

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

Position	Type	Phenotype	Significance	ClinVar
3-47017099-TA-T			Uncertain significance (Jul 06, 2022)
3-47017103-T-C		Luscan-Lumish syndrome	Uncertain significance (Oct 20, 2019)
3-47017106-G-A		Luscan-Lumish syndrome	Likely benign (Jun 13, 2022)
3-47017128-C-T		Luscan-Lumish syndrome • Inborn genetic diseases • not specified	Conflicting classifications of pathogenicity (Jun 20, 2023)
3-47017139-T-G		Luscan-Lumish syndrome	Likely benign (Jun 23, 2022)
3-47017146-T-C			Uncertain significance (Mar 14, 2023)
3-47017163-T-G		Luscan-Lumish syndrome	Likely benign (Jan 13, 2022)
3-47017180-C-T		Luscan-Lumish syndrome	Likely benign (Oct 18, 2022)
3-47017186-C-T		Luscan-Lumish syndrome	Likely benign (Aug 23, 2022)
3-47017255-C-A			Likely pathogenic (Oct 05, 2016)
3-47017656-A-G		Luscan-Lumish syndrome	Likely benign (Jan 22, 2024)
3-47017671-G-A		Luscan-Lumish syndrome	Likely benign (Jan 18, 2024)
3-47017703-G-A		Luscan-Lumish syndrome	Uncertain significance (Jun 05, 2022)
3-47017704-G-A		Luscan-Lumish syndrome	Likely benign (Nov 22, 2022)
3-47017707-A-T		Luscan-Lumish syndrome	Likely benign (Dec 26, 2018)
3-47017724-C-A			Uncertain significance (Aug 29, 2019)
3-47017724-C-T		Luscan-Lumish syndrome • Inborn genetic diseases	Conflicting classifications of pathogenicity (Sep 07, 2022)
3-47017725-G-A		Luscan-Lumish syndrome	Likely benign (May 23, 2019)
3-47017727-T-C			Uncertain significance (Oct 24, 2018)
3-47017732-T-TC			Pathogenic (Jul 19, 2018)
3-47017743-C-G			Uncertain significance (Oct 24, 2019)
3-47017749-G-A		Luscan-Lumish syndrome	Likely benign (Jul 27, 2023)
3-47017833-C-T			Benign (Jul 06, 2018)
3-47017841-T-A			Likely benign (Oct 02, 2018)
3-47019693-G-A			Benign (Aug 03, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SETD2	protein_coding	protein_coding	ENST00000409792	21	147539

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.01e-7	125731	0	17	125748	0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.05	1011	1.32e+3	0.764	0.0000687	16825
Missense in Polyphen		263	496.46	0.52975		6221
Synonymous	0.452	459	471	0.974	0.0000239	4934
Loss of Function	8.30	14	106	0.132	0.00000611	1389

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.000496	0.000496
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000971	0.0000967
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Histone methyltransferase that specifically trimethylates 'Lys-36' of histone H3 (H3K36me3) using dimethylated 'Lys-36' (H3K36me2) as substrate (PubMed:16118227, PubMed:19141475, PubMed:21526191, PubMed:21792193, PubMed:23043551, PubMed:27474439). Represents the main enzyme generating H3K36me3, a specific tag for epigenetic transcriptional activation (By similarity). Plays a role in chromatin structure modulation during elongation by coordinating recruitment of the FACT complex and by interacting with hyperphosphorylated POLR2A (PubMed:23325844). Acts as a key regulator of DNA mismatch repair in G1 and early S phase by generating H3K36me3, a mark required to recruit MSH6 subunit of the MutS alpha complex: early recruitment of the MutS alpha complex to chromatin to be replicated allows a quick identification of mismatch DNA to initiate the mismatch repair reaction (PubMed:23622243). Required for DNA double-strand break repair in response to DNA damage: acts by mediating formation of H3K36me3, promoting recruitment of RAD51 and DNA repair via homologous recombination (HR) (PubMed:24843002). Acts as a tumor suppressor (PubMed:24509477). H3K36me3 also plays an essential role in the maintenance of a heterochromatic state, by recruiting DNA methyltransferase DNMT3A (PubMed:27317772). H3K36me3 is also enhanced in intron-containing genes, suggesting that SETD2 recruitment is enhanced by splicing and that splicing is coupled to recruitment of elongating RNA polymerase (PubMed:21792193). Required during angiogenesis (By similarity). Required for endoderm development by promoting embryonic stem cell differentiation toward endoderm: acts by mediating formation of H3K36me3 in distal promoter regions of FGFR3, leading to regulate transcription initiation of FGFR3 (By similarity). In addition to histones, also mediates methylation of other proteins, such as tubulins and STAT1 (PubMed:27518565, PubMed:28753426). Trimethylates 'Lys-40' of alpha-tubulins such as TUBA1B (alpha- TubK40me3); alpha-TubK40me3 is required for normal mitosis and cytokinesis and may be a specific tag in cytoskeletal remodeling (PubMed:27518565). Involved in interferon-alpha-induced antiviral defense by mediating both monomethylation of STAT1 at 'Lys-525' and catalyzing H3K36me3 on promoters of some interferon-stimulated genes (ISGs) to activate gene transcription (PubMed:28753426). {ECO:0000250|UniProtKB:E9Q5F9, ECO:0000269|PubMed:16118227, ECO:0000269|PubMed:19141475, ECO:0000269|PubMed:21526191, ECO:0000269|PubMed:21792193, ECO:0000269|PubMed:23043551, ECO:0000269|PubMed:23325844, ECO:0000269|PubMed:23622243, ECO:0000269|PubMed:24509477, ECO:0000269|PubMed:24843002, ECO:0000269|PubMed:27317772, ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:27518565, ECO:0000269|PubMed:28753426}.
• Disease: DISEASE: Renal cell carcinoma (RCC) [MIM:144700]: Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. Clear cell renal cell carcinoma is the most common subtype. {ECO:0000269|PubMed:20054297, ECO:0000269|PubMed:23622243, ECO:0000269|PubMed:23792563, ECO:0000269|PubMed:25728682}. Note=The disease may be caused by mutations affecting the gene represented in this entry. Defects of SETD2 are associated with loss of DNA methylation at non-promoter regions (PubMed:23792563). SETD2 defects lead to aberrant and reduced nucleosome compaction and chromatin association of key replication proteins, such as MCM7 and DNA polymerase delta, leading to hinder replication fork progression and prevent loading of RAD51 homologous recombination repair factor at DNA breaks (PubMed:25728682). {ECO:0000269|PubMed:23792563, ECO:0000269|PubMed:25728682}.; DISEASE: Luscan-Lumish syndrome (LLS) [MIM:616831]: An autosomal dominant syndrome with a variable phenotype. Clinical features include macrocephaly, distinctive facial appearance, postnatal overgrowth, various degrees of learning difficulties, autism spectrum disorder, and intellectual disability. {ECO:0000269|PubMed:23160955, ECO:0000269|PubMed:24852293, ECO:0000269|PubMed:26084711, ECO:0000269|PubMed:27317772}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Leukemia, acute lymphoblastic (ALL) [MIM:613065]: A subtype of acute leukemia, a cancer of the white blood cells. ALL is a malignant disease of bone marrow and the most common malignancy diagnosed in children. The malignant cells are lymphoid precursor cells (lymphoblasts) that are arrested in an early stage of development. The lymphoblasts replace the normal marrow elements, resulting in a marked decrease in the production of normal blood cells. Consequently, anemia, thrombocytopenia, and neutropenia occur to varying degrees. The lymphoblasts also proliferate in organs other than the marrow, particularly the liver, spleen, and lymphnodes. {ECO:0000269|PubMed:24509477, ECO:0000269|PubMed:24662245}. Note=The disease may be caused by mutations affecting distinct genetic loci, including the gene represented in this entry.; DISEASE: Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. {ECO:0000269|PubMed:16314571, ECO:0000269|PubMed:24509477}. Note=The disease may be caused by mutations affecting distinct genetic loci, including the gene represented in this entry.
• Pathway: Lysine degradation - Homo sapiens (human);Histone Modifications;Mesodermal Commitment Pathway;Pathways Affected in Adenoid Cystic Carcinoma;Pathways in clear cell renal cell carcinoma;Type 2 papillary renal cell carcinoma;PKMTs methylate histone lysines;Chromatin modifying enzymes;Lysine metabolism;Chromatin organization (Consensus)

Recessive Scores

• pRec: 0.390

Intolerance Scores

• loftool: 0.0294
• rvis_EVS: -0.94
• rvis_percentile_EVS: 9.42

Haploinsufficiency Scores

• pHI: 0.503
• hipred: Y
• hipred_score: 0.611
• ghis: 0.615

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.511

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Setd2
• Phenotype: homeostasis/metabolism phenotype; craniofacial phenotype; growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); immune system phenotype; skeleton 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); limbs/digits/tail phenotype; vision/eye 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); 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); hematopoietic system phenotype; embryo phenotype

Gene ontology

• Biological process: angiogenesis;morphogenesis of a branching structure;neural tube closure;mismatch repair;regulation of transcription, DNA-templated;transcription elongation from RNA polymerase II promoter;regulation of double-strand break repair via homologous recombination;regulation of mRNA export from nucleus;peptidyl-lysine trimethylation;peptidyl-lysine monomethylation;forebrain development;regulation of cytokinesis;positive regulation of interferon-alpha production;response to type I interferon;nucleosome organization;cell migration involved in vasculogenesis;endodermal cell differentiation;mesoderm morphogenesis;embryonic cranial skeleton morphogenesis;stem cell differentiation;stem cell development;defense response to virus;pericardium development;embryonic placenta morphogenesis;coronary vasculature morphogenesis;histone H3-K36 trimethylation;histone H3-K36 dimethylation;microtubule cytoskeleton organization involved in mitosis;regulation of protein localization to chromatin
• Cellular component: nucleus;nucleoplasm;chromosome
• Molecular function: protein binding;protein-lysine N-methyltransferase activity;histone-lysine N-methyltransferase activity;alpha-tubulin binding;metal ion binding;histone methyltransferase activity (H3-K36 specific)