ISCA2

iron-sulfur cluster assembly 2, the group of Mitochondrial iron-sulfur assembly components

Basic information

Region (hg38): 14:74493756-74497106

Previous symbols: [ "HBLD1" ]

Links

ENSG00000165898

∙ NCBI:122961 ∙ OMIM:615317 ∙ HGNC:19857 ∙ Uniprot:Q86U28 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

multiple mitochondrial dysfunctions syndrome 4 (Strong), mode of inheritance: AR
multiple mitochondrial dysfunctions syndrome 4 (Moderate), mode of inheritance: AR
multiple mitochondrial dysfunctions syndrome 4 (Strong), mode of inheritance: AR
multiple mitochondrial dysfunctions syndrome 4 (Supportive), mode of inheritance: AR
mitochondrial disease (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Multiple mitochondrial dysfunctions syndrome 4	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; Variants may additionally act as susceptibility factors (rather than being involved in Mendelian-inherited dominant disease)	Biochemical; Musculoskeletal; Neurologic; Ophthalmologic	25539947

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ISCA2 gene.

not_provided (59 variants)
Inborn_genetic_diseases (20 variants)
Multiple_mitochondrial_dysfunctions_syndrome_4 (11 variants)
not_specified (5 variants)
ISCA2-related_disorder (4 variants)
Fatal_multiple_mitochondrial_dysfunctions_syndrome (1 variants)
Optic_atrophy (1 variants)
Global_developmental_delay (1 variants)
Neurodegeration (1 variants)
Spastic_quadriplegic_cerebral_palsy (1 variants)
High_CSF_lactic_acid (1 variants)
Death_in_infancy (1 variants)
Axial_hypotonia (1 variants)
Failure_to_thrive (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ISCA2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000194279.4. Only rare variants are included in the table.

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.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous				17 clinvar		17
missense		3 clinvar	39 clinvar	2 clinvar		44
nonsense	1 clinvar	1 clinvar				2
start loss						0
frameshift		1 clinvar	2 clinvar			3
splice donor/acceptor (+/-2bp)						0
Total	1	5	41	19	0

Highest pathogenic variant AF is 0.00006630659

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ISCA2	protein_coding	protein_coding	ENST00000556816	4	3387

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.43e-8	0.0445	125725	0	23	125748	0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.384	71	80.7	0.880	0.00000366	971
Missense in Polyphen		20	25.615	0.78078		319
Synonymous	-1.12	43	34.6	1.24	0.00000165	318
Loss of Function	-1.01	10	7.09	1.41	3.54e-7	75

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000235	0.000235
Ashkenazi Jewish	0.00	0.00
East Asian	0.000229	0.000217
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000793	0.0000791
Middle Eastern	0.000229	0.000217
South Asian	0.00	0.00
Other	0.000354	0.000326

dbNSFP

Source: dbNSFP

Function: FUNCTION: Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway. May be involved in the binding of an intermediate of Fe/S cluster assembly. {ECO:0000269|PubMed:22323289}.;
Disease: DISEASE: Multiple mitochondrial dysfunctions syndrome 4 (MMDS4) [MIM:616370]: A severe disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, hyperglycinemia and early death. {ECO:0000269|PubMed:25539947}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Mitochondrial iron-sulfur cluster biogenesis;Metabolism (Consensus)

Intolerance Scores

loftool: 0.530
rvis_EVS: 0.08
rvis_percentile_EVS: 59.43

Haploinsufficiency Scores

pHI: 0.133
hipred: N
hipred_score: 0.239
ghis: 0.607

Essentials

essential_gene_CRISPR: E
essential_gene_CRISPR2: S
essential_gene_gene_trap: H
gene_indispensability_pred: N
gene_indispensability_score: 0.114

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Isca2
Phenotype

Gene ontology

Biological process: iron-sulfur cluster assembly;small molecule metabolic process;protein maturation;protein maturation by iron-sulfur cluster transfer;protein maturation by [4Fe-4S] cluster transfer
Cellular component: mitochondrion;mitochondrial matrix
Molecular function: structural molecule activity;iron ion binding;protein binding;2 iron, 2 sulfur cluster binding;4 iron, 4 sulfur cluster binding