NSD2

nuclear receptor binding SET domain protein 2, the group of PHD finger proteins|SET domain containing|PWWP domain containing|Lysine methyltransferases

Basic information

Region (hg38): 4:1871393-1982207

Previous symbols: [ "WHSC1" ]

Links

ENSG00000109685 ∙ NCBI:7468 ∙ OMIM:602952 ∙ HGNC:12766 ∙ Uniprot:O96028 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Wolf-Hirschhorn syndrome (Definitive), mode of inheritance: AD
• Rauch-Steindl syndrome (Limited), mode of inheritance: AD
• Rauch-Steindl syndrome (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
Rauch-Steindl 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	29760529; 29892088; 30345613; 31171569; 31382906; 33276791; 33941880

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NSD2 gene.

• not provided (14 variants)
• Rauch-Steindl syndrome (11 variants)
• 4p partial monosomy syndrome (6 variants)
• Wolf-Hirschhorn like syndrome (3 variants)
• Syndromic intellectual disability (1 variants)
• Global developmental delay (1 variants)
• NSD2-related disorder (1 variants)
• Neurodevelopmental delay (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NSD2 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	116	13	132
missense	1	6	128	33	5	173
nonsense	11	3	3			17
start loss						0
frameshift	16	6		1		23
inframe indel	1			1		2
splice donor/acceptor (+/-2bp)	1		1			2
splice region			8	11	4	23
non coding			9	38	14	61
Total	30	15	144	189	32

Highest pathogenic variant AF is 0.00000658

Variants in NSD2

This is a list of pathogenic ClinVar variants found in the NSD2 region.

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

Position	Type	Phenotype	Significance	ClinVar
4-1893718-A-AT		4p partial monosomy syndrome	Uncertain significance (Jun 14, 2016)
4-1900624-A-G		Rauch-Steindl syndrome	Uncertain significance (Nov 29, 2023)
4-1900663-T-G			Uncertain significance (Mar 21, 2018)
4-1900665-G-A		Inborn genetic diseases	Conflicting classifications of pathogenicity (Dec 09, 2023)
4-1900678-T-TC		Rauch-Steindl syndrome	Pathogenic (Jun 26, 2023)
4-1900682-C-G		Inborn genetic diseases	Uncertain significance (Jul 23, 2021)
4-1900682-C-T			Uncertain significance (Apr 26, 2023)
4-1900686-C-G		Inborn genetic diseases	Uncertain significance (Dec 20, 2023)
4-1900692-A-G			Uncertain significance (Jan 10, 2024)
4-1900699-TGTAAA-T			Uncertain significance (Apr 13, 2024)
4-1900705-G-C		Inborn genetic diseases	Uncertain significance (Jun 21, 2021)
4-1900722-A-G		Inborn genetic diseases	Uncertain significance (Apr 29, 2024)
4-1900726-A-G			Likely benign (Apr 11, 2022)
4-1900731-A-C			Uncertain significance (Mar 17, 2022)
4-1900734-T-G			Uncertain significance (Apr 11, 2019)
4-1900738-C-T			Likely benign (Jul 17, 2023)
4-1900739-G-A			Uncertain significance (Jan 04, 2022)
4-1900742-A-G		NSD2-related disorder	Uncertain significance (Sep 25, 2023)
4-1900743-G-T			Uncertain significance (May 27, 2022)
4-1900750-C-T			Likely benign (Sep 25, 2023)
4-1900808-C-T		Rauch-Steindl syndrome	Pathogenic (May 28, 2024)
4-1900823-C-T			Likely benign (Aug 20, 2022)
4-1900825-G-T			Likely benign (Jun 25, 2023)
4-1900827-A-C			Uncertain significance (Feb 16, 2024)
4-1900834-G-A			Likely benign (Jun 22, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NSD2	protein_coding	protein_coding	ENST00000382895	21	110784

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	6.25e-9	125734	0	11	125745	0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.90	498	810	0.615	0.0000487	9005
Missense in Polyphen		92	327.44	0.28097		3571
Synonymous	-1.94	364	320	1.14	0.0000216	2564
Loss of Function	7.14	3	65.3	0.0459	0.00000346	778

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000186	0.000186
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000449	0.0000440
Middle Eastern	0.00	0.00
South Asian	0.0000340	0.0000327
Other	0.000164	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Histone methyltransferase with histone H3 'Lys-27' (H3K27me) methyltransferase activity. Isoform 2 may act as a transcription regulator that binds DNA and suppresses IL5 transcription through HDAC recruitment. {ECO:0000269|PubMed:11152655, ECO:0000269|PubMed:16115125, ECO:0000269|PubMed:18172012}.
• Disease: DISEASE: Note=NSD2 is located in the Wolf-Hirschhorn syndrome (WHS) critical region. WHS results from by sub-telomeric deletions in the short arm of chromosome 4. NSD2 is deleted in every case, however deletion of linked genes contributes to both the severity of the core characteristics and the presence of the additional syndromic problems.
• Pathway: Lysine degradation - Homo sapiens (human);Transcriptional misregulation in cancer - Homo sapiens (human);HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);DNA Repair;Nonhomologous End-Joining (NHEJ);DNA Double-Strand Break Repair;Homology Directed Repair;PKMTs methylate histone lysines;G2/M DNA damage checkpoint;Chromatin modifying enzymes;G2/M Checkpoints;Cell Cycle Checkpoints;AndrogenReceptor;Lysine metabolism;Chromatin organization;Cell Cycle;Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks;DNA Double Strand Break Response;Processing of DNA double-strand break ends (Consensus)

Intolerance Scores

• rvis_EVS: -1.37
• rvis_percentile_EVS: 4.48

Haploinsufficiency Scores

• pHI: 0.407
• hipred: Y
• hipred_score: 0.825
• ghis: 0.638

Essentials

• essential_gene_gene_trap: N

Mouse Genome Informatics

• Gene name: Nsd2
• 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); skeleton phenotype; digestive/alimentary phenotype; craniofacial phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: nsd2
• Affected structure: motor neuron
• Phenotype tag: abnormal
• Phenotype quality: truncated

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;membranous septum morphogenesis;atrial septum primum morphogenesis;atrial septum secundum morphogenesis;double-strand break repair via nonhomologous end joining;regulation of transcription, DNA-templated;histone H3-K36 methylation;histone H4-K20 methylation;positive regulation of isotype switching to IgA isotypes;bone development;regulation of establishment of protein localization;regulation of double-strand break repair via nonhomologous end joining
• Cellular component: chromatin;nucleus;nucleoplasm;chromosome;cytoplasm
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;chromatin binding;protein binding;histone-lysine N-methyltransferase activity;histone methyltransferase activity (H4-K20 specific);sequence-specific DNA binding;metal ion binding;histone methyltransferase activity (H3-K36 specific)