CHCHD2

protein-coding

coiled-coil-helix-coiled-coil-helix domain containing 2, the group of Coiled-coil-helix-coiled-coil-helix domain containing proteins

Gene summary

The protein encoded by this gene belongs to a class of eukaryotic CX(9)C proteins characterized by four cysteine residues spaced ten amino acids apart from one another. These residues form disulfide linkages that define a CHCH fold. In response to stress, the protein translocates from the mitochondrial intermembrane space to the nucleus where it binds to a highly conserved 13 nucleotide oxygen responsive element in the promoter of cytochrome oxidase 4I2, a subunit of the terminal enzyme of the electron transport chain. In concert with recombination signal sequence-binding protein J, binding of this protein activates the oxygen responsive element at four percent oxygen. In addition, it has been shown that this protein is a negative regulator of mitochondria-mediated apoptosis. In response to apoptotic stimuli, mitochondrial levels of this protein decrease, allowing BCL2-associated X protein to oligomerize and activate the caspase cascade. Pseudogenes of this gene are found on multiple chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

Previous symbols:

C7orf17

MANE transcript

NM_016139.4

Inheritance

ClinVar variants

P:1U:68B:13

Top phenotype

Parkinson disease 22, autosomal dominant

gnomAD constraint

pLI —, LoF o/e 1.36

Max pathogenic AF

—

Genomic locus

chr7:56,094,567-56,106,479

External References & Databases

Ensembl (ENSG00000106153)

Transcript & Mutation Effects

hg38 • Region Span ~11.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Parkinson disease 22, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014742

Submitter: Labcorp Genetics (formerly Invitae)

Parkinson disease 22, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014742

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Parkinson disease 22, autosomal dominantAD

Manifestation: Neurologic

Intervention: Neurologic

Rationale: Response to levodopa has been described

Refs: 25662902

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CHCHD2 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 75

not specifiedTotal: 20

Parkinson disease 22, autosomal dominantTotal: 5

CHCHD2-related disorderTotal: 5

Amelogenesis imperfectaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016139.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	10 clinvar		11
missense	1 clinvar		62 clinvar	2 clinvar	1 clinvar	66
nonsense			1 clinvar			1
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	0	68	12	1	82

Highest pathogenic variant AF is 0.000008222738

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016139.4	RefSeq	NP_057223.1	4	MANE Select
ENST00000395422.4	Ensembl	ENSP00000378812.3	4	MANE Select
NM_001320327.2	RefSeq	NP_001307256.1	4	Standard
ENST00000716930.1	Ensembl	ENSP00000520614.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of proteins
Mitochondrial protein import

Biological Process

mitochondrion organization
positive regulation of transcription by RNA polymerase II
regulation of cellular response to hypoxia

Molecular Function

protein binding
transcription factor binding
sequence-specific DNA binding

Cellular Component

nucleus
mitochondrion
mitochondrial intermembrane space

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000395422
Coding exons: 4
Length: 5008
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125747
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.121	88	91.3	0.964	0.00000484	950
Missense (PolyPhen)		14	20.725	0.67553		265
Synonymous	0.468	32	35.5	0.900	0.00000202	329
Loss of Function	-0.855	9	6.63	1.36	2.88e-7	67

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor. Binds to the oxygen responsive element of COX4I2 and activates its transcription under hypoxia conditions (4% oxygen), as well as normoxia conditions (20% oxygen) (PubMed:23303788). {ECO:0000269|PubMed:23303788}.;
Disease: DISEASE: Parkinson disease 22 (PARK22) [MIM:616710]: An autosomal dominant form of Parkinson disease, a complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. {ECO:0000269|PubMed:25662902}. Note=The gene represented in this entry may be involved in disease pathogenesis.;

Recessive Scores

pRec: 0.100

Intolerance Scores

LoFtool: 0.686
RVIS EVS: -0.12
RVIS percentile EVS: 44.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.942

Gene Damage Prediction

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