NSMCE2

NSE2 (MMS21) homolog, SMC5-SMC6 complex SUMO ligase, the group of Zinc fingers MIZ-type|SMC5-6 protein complex

Basic information

Region (hg38): 8:125091679-125367125

Previous symbols: [ "C8orf36" ]

Links

ENSG00000156831 ∙ NCBI:286053 ∙ OMIM:617246 ∙ HGNC:26513 ∙ Uniprot:Q96MF7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• microcephalic primordial dwarfism-insulin resistance syndrome (Supportive), mode of inheritance: AR
• Seckel syndrome 10 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Seckel syndrome 10	AR	Cardiovascular; Musculoskeletal	Among other features, individuals have been described with childhood-onset hypertriglyceridemia, and awareness may allow early diagnosis and dietary/medical management; An individual has been described with aortic aneurysm, and awareness may allow surveillance and early diagnosis and management	Cardiovascular; Craniofacial; Endocrine; Musculoskeletal	25105364

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NSMCE2 gene.

• not provided (4 variants)
• Seckel syndrome 10 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NSMCE2 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				15	1	16
missense			27	2	1	30
nonsense	2					2
start loss						0
frameshift	2					2
inframe indel			1			1
splice donor/acceptor (+/-2bp)		1				1
splice region			3		1	4
non coding				16	1	17
Total	4	1	28	33	3

Highest pathogenic variant AF is 0.000197

Variants in NSMCE2

This is a list of pathogenic ClinVar variants found in the NSMCE2 region.

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

Position	Type	Phenotype	Significance	ClinVar
8-125091709-C-G		Hereditary spastic paraplegia 8	Uncertain significance (Jan 13, 2018)
8-125091731-C-T		Hereditary spastic paraplegia 8	Benign (Jan 12, 2018)
8-125091735-G-C		Hereditary spastic paraplegia 8	Benign (Jan 12, 2018)
8-125091743-C-T		Hereditary spastic paraplegia 8	Benign (Jan 13, 2018)
8-125091766-C-T		Hereditary spastic paraplegia 8	Uncertain significance (Jan 12, 2018)
8-125102340-C-T		not specified	Uncertain significance (Jul 26, 2024)
8-125102350-C-G			Pathogenic (May 23, 2023)
8-125102364-A-G			Uncertain significance (Mar 13, 2022)
8-125102366-T-C			Likely benign (Oct 23, 2023)
8-125102368-G-A			Uncertain significance (Feb 28, 2022)
8-125102374-TCTC-T			Uncertain significance (Feb 04, 2022)
8-125102377-C-T			Uncertain significance (Aug 09, 2022)
8-125102393-G-A			Likely benign (Jan 17, 2024)
8-125102414-A-G			Likely benign (Apr 15, 2022)
8-125102444-G-C			Uncertain significance (Oct 17, 2022)
8-125102448-A-G			Uncertain significance (Nov 01, 2023)
8-125102455-C-T		not specified	Uncertain significance (Mar 15, 2024)
8-125102475-G-A		not specified	Uncertain significance (Dec 13, 2022)
8-125151151-G-A			Likely benign (Oct 27, 2022)
8-125151154-A-G			Benign (Jan 18, 2024)
8-125151154-A-AT			Benign (Jan 21, 2024)
8-125151157-T-G			Likely benign (Apr 26, 2023)
8-125151183-G-A			Uncertain significance (Mar 19, 2022)
8-125151194-A-G		not specified	Uncertain significance (Jun 22, 2023)
8-125151227-G-A			Uncertain significance (Dec 22, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NSMCE2	protein_coding	protein_coding	ENST00000287437	6	275442

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0379	0.932	125671	0	75	125746	0.000298

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.815	109	136	0.803	0.00000704	1660
Missense in Polyphen		24	37.003	0.64859		474
Synonymous	-0.358	47	44.0	1.07	0.00000226	427
Loss of Function	1.88	4	10.6	0.377	4.45e-7	147

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000270	0.000268
Ashkenazi Jewish	0.000100	0.0000992
East Asian	0.000339	0.000326
Finnish	0.0000470	0.0000462
European (Non-Finnish)	0.000513	0.000492
Middle Eastern	0.000339	0.000326
South Asian	0.00	0.00
Other	0.000498	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: E3 SUMO-protein ligase component of the SMC5-SMC6 complex, a complex involved in DNA double-strand break repair by homologous recombination. Is not be required for the stability of the complex. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs). Acts as an E3 ligase mediating SUMO attachment to various proteins such as SMC6L1 and TRAX, the shelterin complex subunits TERF1, TERF2, TINF2 and TERF2IP, and maybe the cohesin components RAD21 and STAG2. Required for recruitment of telomeres to PML nuclear bodies. SUMO protein-ligase activity is required for the prevention of DNA damage-induced apoptosis by facilitating DNA repair, and for formation of APBs in ALT cell lines. Required for sister chromatid cohesion during prometaphase and mitotic progression. {ECO:0000269|PubMed:16055714, ECO:0000269|PubMed:16810316, ECO:0000269|PubMed:17589526, ECO:0000269|PubMed:19502785}.
• Disease: DISEASE: Seckel syndrome 10 (SCKL10) [MIM:617253]: A form of Seckel syndrome, a rare autosomal recessive disorder characterized by proportionate dwarfism of prenatal onset associated with low birth weight, growth retardation, severe microcephaly with a bird- headed like appearance, and mental retardation. {ECO:0000269|PubMed:25105364}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: SUMOylation of DNA damage response and repair proteins;Post-translational protein modification;SUMO E3 ligases SUMOylate target proteins;Metabolism of proteins;SUMOylation (Consensus)

Recessive Scores

• pRec: 0.0905

Intolerance Scores

• loftool: 0.614
• rvis_EVS: -0.07
• rvis_percentile_EVS: 48.12

Haploinsufficiency Scores

• pHI: 0.0687
• hipred: N
• hipred_score: 0.244
• ghis: 0.578

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: H
• gene_indispensability_pred: N
• gene_indispensability_score: 0.461

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nsmce2
• 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); normal phenotype; 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; neoplasm; pigmentation phenotype; embryo phenotype; liver/biliary system phenotype; immune system phenotype; digestive/alimentary phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); 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); endocrine/exocrine gland phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: nsmce2
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: decreased length

Gene ontology

• Biological process: telomere maintenance via recombination;double-strand break repair via homologous recombination;double-strand break repair via nonhomologous end joining;cell cycle;protein sumoylation;positive regulation of maintenance of mitotic sister chromatid cohesion;positive regulation of mitotic metaphase/anaphase transition;cell division;cellular senescence
• Cellular component: chromosome, telomeric region;nucleus;nucleoplasm;nuclear body;PML body;Smc5-Smc6 complex
• Molecular function: protein binding;zinc ion binding;SUMO transferase activity