SETD2
SET domain containing 2, histone lysine methyltransferase, the group of SET domain containing|Lysine methyltransferases
Basic information
Region (hg38): 3:47016428-47164113
Links
Phenotypes
GenCC
Source:
- 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:
| 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
- Luscan-Lumish syndrome (13 variants)
- not provided (9 variants)
- Inborn genetic diseases (4 variants)
- Intellectual disability (1 variants)
- Intellectual developmental disorder, autosomal dominant 70 (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 | 201 | 11 | 220 | |||
| missense | 484 | 101 | 45 | 636 | ||
| nonsense | 12 | 17 | ||||
| start loss | 2 | |||||
| frameshift | 10 | 18 | ||||
| inframe indel | 10 | 13 | ||||
| splice donor/acceptor (+/-2bp) | 3 | |||||
| splice region | 7 | 11 | 1 | 19 | ||
| non coding | 54 | 42 | 98 | |||
| Total | 25 | 16 | 508 | 360 | 98 |
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) | ||
| 3-47017164-C-G | Uncertain significance (Feb 23, 2024) | |||
| 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) | |||
| 3-47017642-C-T | Uncertain significance (Feb 20, 2024) | |||
| 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) |
GnomAD
Source:
| 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:
- 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)