MICU1

mitochondrial calcium uptake 1, the group of EF-hand domain containing

Basic information

Region (hg38): 10:72367339-72626131

Previous symbols: [ "CBARA1" ]

Links

ENSG00000107745 ∙ NCBI:10367 ∙ OMIM:605084 ∙ HGNC:1530 ∙ Uniprot:Q9BPX6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• proximal myopathy with extrapyramidal signs (Definitive), mode of inheritance: AR
• proximal myopathy with extrapyramidal signs (Definitive), mode of inheritance: AR
• proximal myopathy with extrapyramidal signs (Strong), mode of inheritance: AR
• proximal myopathy with extrapyramidal signs (Supportive), mode of inheritance: AR
• proximal myopathy with extrapyramidal signs (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Myopathy with extrapyramidal signs	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	Musculoskeletal; Neurologic	24336167; 27123478; 29721912

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MICU1 gene.

• not provided (221 variants)
• Proximal myopathy with extrapyramidal signs (13 variants)
• Inborn genetic diseases (12 variants)
• not specified (6 variants)
• Neurodevelopmental disorder (2 variants)
• Abnormality of the nervous system (1 variants)
• MICU1-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MICU1 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			1	36	2	39
missense		1	73	1	1	76
nonsense	6	2				8
start loss						0
frameshift	8	2				10
inframe indel			2			2
splice donor/acceptor (+/-2bp)	2	9				11
splice region			4	6	2	12
non coding	1		2	48	29	80
Total	17	14	78	85	32

Highest pathogenic variant AF is 0.0000591

Variants in MICU1

This is a list of pathogenic ClinVar variants found in the MICU1 region.

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

Position	Type	Phenotype	Significance	ClinVar
10-72368083-C-T			Benign (Jun 16, 2018)
10-72368095-G-A			Benign (Jun 23, 2018)
10-72368105-C-G			Likely benign (Jun 14, 2018)
10-72368194-G-T			Likely benign (Feb 14, 2019)
10-72368201-T-C			Likely benign (Oct 10, 2023)
10-72368212-C-T			Uncertain significance (Sep 09, 2019)
10-72368213-G-A			Likely benign (Aug 01, 2023)
10-72368216-G-A			Likely benign (Feb 21, 2022)
10-72368232-T-G			Uncertain significance (Dec 26, 2021)
10-72368248-T-C			Uncertain significance (Aug 23, 2022)
10-72368254-G-T			Uncertain significance (Jun 02, 2022)
10-72368285-C-T			Likely benign (Apr 01, 2023)
10-72368303-C-T			Likely benign (Mar 02, 2023)
10-72368307-C-T			Uncertain significance (Sep 20, 2023)
10-72368309-T-C			Uncertain significance (Oct 27, 2021)
10-72368312-C-T			Likely benign (Jun 26, 2022)
10-72368347-C-T			Uncertain significance (Mar 15, 2023)
10-72368348-G-A			Likely benign (Jan 05, 2024)
10-72368348-G-T			Likely benign (May 23, 2023)
10-72368352-T-C			Uncertain significance (Feb 23, 2022)
10-72368372-AAAC-A			Likely benign (Aug 24, 2023)
10-72368375-C-G			Likely benign (Jun 15, 2023)
10-72368386-A-C			Likely benign (Sep 04, 2018)
10-72368395-C-T			Benign (Jun 16, 2018)
10-72368473-C-T			Benign (Jun 14, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MICU1	protein_coding	protein_coding	ENST00000361114	11	258802

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.93e-13	0.0593	124581	0	63	124644	0.000253

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.65	174	247	0.704	0.0000130	3145
Missense in Polyphen		31	67.052	0.46233		844
Synonymous	0.839	73	82.7	0.883	0.00000402	873
Loss of Function	0.465	21	23.4	0.896	0.00000145	280

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000459	0.000456
Ashkenazi Jewish	0.000101	0.0000994
East Asian	0.0000556	0.0000556
Finnish	0.0000478	0.0000464
European (Non-Finnish)	0.000286	0.000274
Middle Eastern	0.0000556	0.0000556
South Asian	0.000530	0.000523
Other	0.000194	0.000165

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Key regulator of mitochondrial calcium uniporter (MCU) that senses calcium level via its EF-hand domains (PubMed:20693986, PubMed:23101630, PubMed:23747253, PubMed:24313810, PubMed:24332854, PubMed:24503055, PubMed:24560927, PubMed:26341627, PubMed:26903221, PubMed:27099988). MICU1 and MICU2 form a disulfide-linked heterodimer that stimulates and inhibits MCU activity, depending on the concentration of calcium. MICU1 acts both as an activator or inhibitor of mitochondrial calcium uptake (PubMed:26903221). Acts as a gatekeeper of MCU at low concentration of calcium, preventing channel opening (PubMed:26903221). Enhances MCU opening at high calcium concentration, allowing a rapid response of mitochondria to calcium signals generated in the cytoplasm (PubMed:24560927, PubMed:26903221). Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake (PubMed:22904319). Induces T-helper 1-mediated autoreactivity, which is accompanied by the release of IFNG (PubMed:16002733). {ECO:0000269|PubMed:16002733, ECO:0000269|PubMed:20693986, ECO:0000269|PubMed:22904319, ECO:0000269|PubMed:23101630, ECO:0000269|PubMed:23747253, ECO:0000269|PubMed:24313810, ECO:0000269|PubMed:24332854, ECO:0000269|PubMed:24503055, ECO:0000269|PubMed:24560927, ECO:0000269|PubMed:26341627, ECO:0000269|PubMed:26903221, ECO:0000269|PubMed:27099988}.
• Disease: DISEASE: Myopathy with extrapyramidal signs (MPXPS) [MIM:615673]: An autosomal recessive disorder characterized by early-onset proximal muscle weakness with a static course and moderately to grossly elevated serum creatine kinase levels accompanied by learning difficulties. Most patients develop subtle extrapyramidal motor signs that progress to a debilitating disorder of involuntary movement with variable features, including chorea, tremor, dystonic posturing and orofacial dyskinesia. Additional variable features include ataxia, microcephaly, ophthalmoplegia, ptosis, optic atrophy and axonal peripheral neuropathy. {ECO:0000269|PubMed:24336167}. Note=The disease is caused by mutations affecting the gene represented in this entry. The complex phenotype is due to alterations in mitochondrial calcium signaling characterized by increased mitochondrial Ca(2+) load (PubMed:24336167). {ECO:0000269|PubMed:24336167}.; DISEASE: Note=An homozygous partial MICU1 deletion is responsible for a disorder manifesting in childhood with fatigue, lethargy and muscle weakness. The disease is caused by mutations affecting the gene represented in this entry. {ECO:0000269|PubMed:27123478}.
• Pathway: Transport of small molecules;Mitochondrial calcium ion transport;Processing of SMDT1 (Consensus)

Recessive Scores

• pRec: 0.158

Intolerance Scores

• rvis_EVS: -0.45
• rvis_percentile_EVS: 24.19

Haploinsufficiency Scores

• pHI: 0.226
• hipred: N
• hipred_score: 0.294
• ghis: 0.570

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• 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: Micu1

Gene ontology

• Biological process: mitochondrial calcium ion transmembrane transport;defense response;calcium import into the mitochondrion;protein homooligomerization;mitochondrial calcium ion homeostasis;positive regulation of mitochondrial calcium ion concentration;calcium ion import
• Cellular component: mitochondrion;mitochondrial inner membrane;mitochondrial intermembrane space;integral component of mitochondrial membrane;calcium channel complex;uniplex complex
• Molecular function: calcium ion binding;protein binding;identical protein binding;protein heterodimerization activity