NSMCE2

protein-coding

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

Gene summary

This gene encodes a member of a family of E3 small ubiquitin-related modifier (SUMO) ligases that mediates the attachment of a SUMO protein to proteins involved in nuclear transport, transcription, chromosome segregation and DNA repair. The encoded protein is part of the structural maintenance of chromosomes (SMC) 5/6 complex which plays a key role genome maintenance, facilitating chromosome segregation and suppressing mitotic recombination. A knockout of the orthologous mouse gene is lethal prior to embryonic day 10.5. Naturally occurring mutations in this gene, that abolish the SUMO ligase activity, are associated with primordial dwarfism and extreme insulin resistance. [provided by RefSeq, Mar 2017]

Previous symbols:

C8orf36

MANE transcript

NM_173685.4

Inheritance

ClinVar variants

P:7U:46B:30

Top phenotype

Seckel syndrome 10

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr8:125,091,679-125,367,125

External References & Databases

Ensembl (ENSG00000156831)

Transcript & Mutation Effects

hg38 • Region Span ~275.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Seckel syndrome 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014991

Submitter: Labcorp Genetics (formerly Invitae)

Seckel syndrome 10MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014991

Submitter: ClinGen

*NSMCE2* is located on chromosome 8q24.13 and encodes a SUMO E3 ligase that functions within the SMC5/6 complex, essential for DNA damage repair, resolution of replication stress, and chromosome stability. It promotes SUMOylation of SMC6, a process enhanced upon DNA damage, linking its activity to the DNA damage response. Pathogenic variants in *NSMCE2* were first reported in two patients with clinical features suggestive of Seckel syndrome, a recessive disorder characterized by poor growth, microcephaly, and intellectual disability, by Payne et al. (2014, PMID: 25105364). Biallelic pathogenic variants in SMC5 that is another cardinal component of SMC5/6 also disrupt NSMCE2 function that was seen in two publications with microcephaly, short stature, and developmental delay due to impaired binding with SMC5, SLF2, and SMC6 (Grange et al, 2022, PMID: 36333305; Zhu et al, PMID: 36627765). Loss of *NSMCE2* results in stalled replication forks, defective double-strand break formation, and chromosomal instability, evidenced by increased micronuclei and nucleoplasmic bridges in fibroblasts. Hydroxyurea treatment exacerbates replication stress, and BrdU pulse-chase experiments in patient-derived lymphoblastoid cell lines reveal impaired S-phase progression. These findings underscore *NSMCE2*’s critical role in genome maintenance and human developmental disorders. Two frameshift variants have been reported in humans and the information of four other variants (frameshift, nonsense and exonic deletion) in *NSMCE2* is available in the ClinVar database. This gene-disease relationship is supported by biochemical function studies, protein interaction, non-human model organism studies, and functional alteration analysis. (Payne et al. 2014, PMID: 25105364; Atkins 2020, PMID: 33200984; Zhu et al, PMID: 36627765). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date February 5th, 2025 (SOP Version 11).

microcephalic primordial dwarfism-insulin resistance syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018575

Submitter: Orphanet

Seckel syndrome 10MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014991

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Seckel syndrome 10AR

Manifestation: Cardiovascular; Craniofacial; Endocrine; Musculoskeletal

Intervention: Cardiovascular; Musculoskeletal

Rationale: 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

Refs: 25105364

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NSMCE2 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 81

not specifiedTotal: 39

Seckel syndrome 10Total: 7

NSMCE2-related disorderTotal: 5

Decreased response to growth hormone stimulation testTotal: 1

Short statureTotal: 1

Dysmorphic featuresTotal: 1

Global developmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_173685.4. 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				26 clinvar		26
missense			45 clinvar	3 clinvar	1 clinvar	49
nonsense	1 clinvar	1 clinvar				2
start loss						0
frameshift	3 clinvar	1 clinvar				4
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	4	3	46	29	1	83

Highest pathogenic variant AF is 0.00022155093

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 89 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_173685.4	RefSeq	NP_775956.1	6	MANE Select
ENST00000287437.8	Ensembl	ENSP00000287437.3	6	MANE Select
NM_001349485.2	RefSeq	NP_001336414.1	6	Standard
NM_001349486.2	RefSeq	NP_001336415.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
nsmce2	Danio rerio	Structure: whole organism Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

nsmce2

Danio rerio

Structure: whole organism

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

SUMOylation of DNA damage response and repair proteins
Post-translational protein modification
SUMO E3 ligases SUMOylate target proteins
Metabolism of proteins
SUMOylation

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

Molecular Function

protein binding
zinc ion binding
SUMO transferase activity

Cellular Component

chromosome, telomeric region
nucleus
nucleoplasm
nuclear body
PML body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000287437
Coding exons: 6
Length: 275442
Individuals with no LoFs: 125671
Homozygous LoFs: 0
Heterozygous LoFs: 75
Defined: 125746
p: 0.000298

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.815	109	136	0.803	0.00000704	1660
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000064	0.000062	rare
Latino/Admixed American	0.00021	0.00020	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00034	0.00033	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00051	0.00049	rare
South Asian	0	0.0	absent
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.0905

Intolerance Scores

LoFtool: 0.614
RVIS EVS: -0.07
RVIS percentile EVS: 48.12

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.461

Gene Damage Prediction

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