NDUFS2

NADH:ubiquinone oxidoreductase core subunit S2, the group of NADH:ubiquinone oxidoreductase core subunits

Basic information

Region (hg38): 1:161197103-161214723

Links

ENSG00000158864 ∙ NCBI:4720 ∙ OMIM:602985 ∙ HGNC:7708 ∙ Uniprot:O75306 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• mitochondrial complex 1 deficiency, nuclear type 6 (Strong), mode of inheritance: AR
• Leber hereditary optic neuropathy (Supportive), mode of inheritance: Mitochondrial
• mitochondrial complex I deficiency (Supportive), mode of inheritance: AR
• Leigh syndrome with cardiomyopathy (Supportive), mode of inheritance: AR
• Leigh syndrome with leukodystrophy (Supportive), mode of inheritance: AR
• mitochondrial complex 1 deficiency, nuclear type 6 (Strong), mode of inheritance: AR
• mitochondrial complex I deficiency, nuclear type 1 (Definitive), mode of inheritance: AR
• mitochondrial complex 1 deficiency, nuclear type 6 (Limited), mode of inheritance: Unknown
• Leigh syndrome (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Mitochondrial complex I deficiency, nuclear type 6; Leber hereditary optic neuropathy, autosomal recessive 2	AR	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	Biochemical; Cardiovascular; Gastrointestinal; Neurologic; Ophthalmologic	11743516; 11220739; 20819849; 22036843; 28031252
In Mitochondrial complex I deficiency, nuclear type 5, medical treatment (eg, riboflavin, ubiquinol) may be beneficial, and individuals may have cardiac involvement

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NDUFS2 gene.

• not provided (161 variants)
• Mitochondrial complex I deficiency, nuclear type 1 (43 variants)
• Mitochondrial complex 1 deficiency, nuclear type 6 (34 variants)
• not specified (33 variants)
• Inborn genetic diseases (27 variants)
• Mitochondrial complex I deficiency (9 variants)
• Leber optic atrophy (1 variants)
• Leber-like hereditary optic neuropathy, autosomal recessive 2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NDUFS2 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	26	1	30
missense	1	3	60	3	1	68
nonsense	1	1				2
start loss						0
frameshift			2			2
inframe indel			1			1
splice donor/acceptor (+/-2bp)		2				2
splice region			11	10		21
non coding			23	28	12	63
Total	2	6	89	57	14

Highest pathogenic variant AF is 0.0000132

Variants in NDUFS2

This is a list of pathogenic ClinVar variants found in the NDUFS2 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-161198003-T-C		not specified	Uncertain significance (Mar 07, 2024)
1-161198080-C-T		not specified	Uncertain significance (Nov 09, 2021)
1-161198083-C-T		not specified	Uncertain significance (Apr 18, 2023)
1-161198101-G-C		not specified	Uncertain significance (Jun 23, 2023)
1-161198252-T-C		not specified	Uncertain significance (Aug 16, 2022)
1-161198327-C-T		not specified	Uncertain significance (Nov 27, 2023)
1-161198330-A-G			Likely benign (Dec 01, 2023)
1-161198356-G-A		not specified	Uncertain significance (Mar 29, 2023)
1-161198377-C-T		not specified	Uncertain significance (Oct 14, 2021)
1-161198401-C-T		not specified	Uncertain significance (Mar 01, 2024)
1-161198407-C-T		not specified	Uncertain significance (Jan 30, 2024)
1-161198423-C-T		not specified	Uncertain significance (May 09, 2023)
1-161198444-C-T		not specified	Uncertain significance (Oct 26, 2021)
1-161198585-G-A		not specified	Likely benign (Jan 12, 2024)
1-161198587-C-T		not specified	Uncertain significance (Jun 23, 2023)
1-161198603-C-T		not specified	Likely benign (Oct 27, 2022)
1-161198608-T-C		not specified	Uncertain significance (May 16, 2022)
1-161199375-G-A		Mitochondrial complex I deficiency, nuclear type 1	Uncertain significance (Jan 13, 2018)
1-161199375-G-T		Mitochondrial complex I deficiency, nuclear type 1 • Mitochondrial complex 1 deficiency, nuclear type 6	Benign (Apr 11, 2023)
1-161199417-G-A		Mitochondrial complex I deficiency, nuclear type 1	Uncertain significance (Jan 13, 2018)
1-161199465-C-G		Mitochondrial complex I deficiency, nuclear type 1	Uncertain significance (Jan 12, 2018)
1-161201946-A-G			Likely benign (Jun 26, 2018)
1-161202163-C-G		not specified • Mitochondrial complex I deficiency, nuclear type 1	Conflicting classifications of pathogenicity (Jan 13, 2018)
1-161202168-G-A		Mitochondrial complex I deficiency, nuclear type 1	Uncertain significance (Jan 13, 2018)
1-161202227-C-A		Mitochondrial complex I deficiency, nuclear type 1	Uncertain significance (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NDUFS2	protein_coding	protein_coding	ENST00000367993	14	17292

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00142	0.999	125722	0	26	125748	0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.47	192	259	0.742	0.0000153	2994
Missense in Polyphen		62	122.48	0.50619		1343
Synonymous	-1.18	108	93.4	1.16	0.00000476	919
Loss of Function	3.50	11	32.5	0.338	0.00000210	320

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000239	0.000239
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.000142	0.000139
European (Non-Finnish)	0.0000705	0.0000703
Middle Eastern	0.00	0.00
South Asian	0.000229	0.000229
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) that is believed to belong to the minimal assembly required for catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone (PubMed:12611891). {ECO:0000269|PubMed:12611891}.
• Disease: DISEASE: Mitochondrial complex I deficiency (MT-C1D) [MIM:252010]: A disorder of the mitochondrial respiratory chain that causes a wide range of clinical manifestations from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. {ECO:0000269|PubMed:11220739}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Retrograde endocannabinoid signaling - Homo sapiens (human);Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human);Alzheimer,s disease - Homo sapiens (human);Huntington,s disease - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Oxidative phosphorylation - Homo sapiens (human);Doxorubicin Pathway, Pharmacokinetics;Parkinson,s disease - Homo sapiens (human);Metformin Pathway, Pharmacodynamic;Doxorubicin Metabolism Pathway;Electron Transport Chain;Oxidative phosphorylation;Respiratory electron transport;The citric acid (TCA) cycle and respiratory electron transport;Metabolism;p73 transcription factor network;Complex I biogenesis;Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins. (Consensus)

Recessive Scores

• pRec: 0.419

Intolerance Scores

• loftool: 0.0524
• rvis_EVS: 0.49
• rvis_percentile_EVS: 79.38

Haploinsufficiency Scores

• pHI: 0.313
• hipred: Y
• hipred_score: 0.642
• ghis: 0.420

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.981

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ndufs2

Gene ontology

• Biological process: mitochondrial electron transport, NADH to ubiquinone;response to oxidative stress;mitochondrial respiratory chain complex I assembly;mitochondrial ATP synthesis coupled electron transport
• Cellular component: nucleoplasm;mitochondrion;mitochondrial respiratory chain complex I;mitochondrial matrix
• Molecular function: NADH dehydrogenase activity;protein binding;NADH dehydrogenase (ubiquinone) activity;electron transfer activity;ubiquitin protein ligase binding;metal ion binding;quinone binding;NAD binding;4 iron, 4 sulfur cluster binding