NSMCE2

Chr 8AR

NSE2 SUMO ligase component of SMC5/6 complex

Also known as: C8orf36, MMS21, NSE2, ZMIZ7

NCBI Gene: 286053 ENSG00000156831 UniProt: Q96MF7 OMIM: 617246

The protein functions as an E3 SUMO ligase within the SMC5-SMC6 complex, mediating DNA double-strand break repair by homologous recombination, telomere maintenance, and sister chromatid cohesion during mitosis. Biallelic mutations cause Seckel syndrome 10, characterized by primordial dwarfism and extreme insulin resistance with prenatal onset. This follows autosomal recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

ARLOEUF 0.861 OMIM phenotype

Clinical Summary— NSMCE2

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Gene-Disease Validity (ClinGen)

Seckel syndrome 10 · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 52 VUS of 119 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.86LOEUF

pLI 0.038

Z-score 1.88

OE 0.38 (0.18–0.86)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.82Z-score

OE missense 0.80 (0.69–0.94)

109 obs / 135.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.18–0.86)

0≤0.351.4

Missense OE?0.80 (0.69–0.94)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 4 / 10.6Missense obs/exp: 109 / 135.7Syn Z: -0.36

ClinVar Variant Classifications

119 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic1

VUS52

Likely Benign47

Benign3

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	0	1	0	7
Likely Pathogenic	1	0	0	0	1
VUS	0	47	5	0	52
Likely Benign	0	6	18	23	47
Benign	0	1	2	0	3
Conflicting	—				1
Total	7	54	26	23	111

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

55 pathogenic / likely-pathogenic (of 67) ClinVar copy-number / structural variants overlap NSMCE2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →