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.

• Inborn genetic diseases (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.

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				14		14
missense		2	26	1		29
nonsense	1	1				2
start loss						0
frameshift			2			2
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region			3	1		4
non coding			2	9	2	13
Total	1	3	31	24	2

Highest pathogenic variant AF is 0.0000394

Variants in ISCA2

This is a list of pathogenic ClinVar variants found in the ISCA2 region.

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

Position	Type	Phenotype	Significance	ClinVar
14-74493769-A-C		not specified	Likely benign (Jun 02, 2016)
14-74493795-G-C			Likely benign (Oct 17, 2023)
14-74493798-C-T			Likely benign (Nov 01, 2022)
14-74493800-T-A			Uncertain significance (May 06, 2024)
14-74493803-C-T			Uncertain significance (Aug 23, 2021)
14-74493807-C-G			Likely benign (Jul 22, 2023)
14-74493808-GCGA-G			Uncertain significance (Jun 01, 2023)
14-74493825-C-A			Likely benign (Dec 03, 2021)
14-74493829-C-T		Inborn genetic diseases	Uncertain significance (Feb 06, 2024)
14-74493836-C-T			Uncertain significance (Dec 11, 2023)
14-74493841-G-C			Uncertain significance (Jun 07, 2022)
14-74493848-A-T		Multiple mitochondrial dysfunctions syndrome 4	Uncertain significance (Mar 29, 2024)
14-74493853-G-A		ISCA2-related disorder	Likely benign (Jan 07, 2020)
14-74493855-C-T			Likely benign (Oct 25, 2021)
14-74493876-G-T			Likely benign (Jul 10, 2018)
14-74494030-C-T			Likely benign (Aug 04, 2023)
14-74494045-C-T			Likely benign (Oct 24, 2020)
14-74494053-C-T			Likely benign (Mar 31, 2021)
14-74494056-C-T			Likely benign (May 29, 2022)
14-74494061-C-T		ISCA2-related disorder	Conflicting classifications of pathogenicity (Feb 13, 2024)
14-74494064-C-T			Uncertain significance (Jan 04, 2024)
14-74494082-G-T			Uncertain significance (May 09, 2024)
14-74494089-G-A			Likely benign (May 06, 2022)
14-74494090-G-A		Inborn genetic diseases	Uncertain significance (Aug 12, 2024)
14-74494094-C-A			Likely pathogenic (Jun 25, 2021)

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

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