CYCS

protein-coding

cytochrome c, somatic

Gene summary

This gene encodes a small heme protein that functions as a central component of the electron transport chain in mitochondria. The encoded protein associates with the inner membrane of the mitochondrion where it accepts electrons from cytochrome b and transfers them to the cytochrome oxidase complex. This protein is also involved in initiation of apoptosis. Mutations in this gene are associated with autosomal dominant nonsyndromic thrombocytopenia. Numerous processed pseudogenes of this gene are found throughout the human genome.[provided by RefSeq, Jul 2010]

MANE transcript

NM_018947.6

Inheritance

ClinVar variants

P:8U:24B:13

Top phenotype

Thrombocytopenia 4

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr7:25,118,656-25,125,260

External References & Databases

Ensembl (ENSG00000172115)

Transcript & Mutation Effects

hg38 • Region Span ~6.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

thrombocytopenia 4LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012775

Submitter: ClinGen

CYCS was first reported in relation to autosomal dominant thrombocytopenia 4 in 2008 (Morison IM, et al., PMID: 18345000). At least 15 unique variants (14 missense and 1 small in-frame deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and segregation data. Variants in this gene have been reported in at least 26 probands in 9 publications (PMIDs: 18345000, 2432610, 27479822, 30051457, 31064749, 32581362, 35126455, 36507135, 34355501) and one ClinVar entry (SCV004104803.1). Variants in this gene segregated with disease in at least 34 additional family members. Experimental evidence of a functional alteration of platelet formation (PMID: 27861742) was shown in patient cells, however the normal function of CYCS in relation to platelet formation remains unclear. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the HT GCEP on 2021 Jun 23. It was reevaluated on 2025 Jan 23. As a result of this reevaluation 11 additional patients were identified (PMIDs: 35126455, 36507135, 34355501, SCV004104803.1) however the classification remained Limited.

thrombocytopenia 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012775

Submitter: Labcorp Genetics (formerly Invitae)

autosomal thrombocytopenia with normal plateletsSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015679

Submitter: Orphanet

thrombocytopenia 4MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012775

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Thrombocytopenia 4AD

Manifestation: Hematologic

Intervention: General

Rationale: Reported clinical findings related to thrombocytopenia were absent or mild; 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

Refs: 18345000; 22102269; 24326104; 30051457

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYCS variants in ClinVar

6 Conditions Cataloged

not providedTotal: 41

Thrombocytopenia 4Total: 14

CYCS-related disorderTotal: 5

not specifiedTotal: 5

ThrombocytopeniaTotal: 4

Abnormal bleedingTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018947.6. 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				13 clinvar		13
missense	1 clinvar	7 clinvar	23 clinvar			31
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	7	24	13	0	45

Highest pathogenic variant AF is 0.0000013681014

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018947.6	RefSeq	NP_061820.1	2	MANE Select
ENST00000305786.7	Ensembl	ENSP00000307786.2	2	MANE Select
ENST00000409409.5	Ensembl	ENSP00000386270.1	2	Standard
ENST00000409409.6	Ensembl	ENSP00000386270.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
Legionellosis - Homo sapiens (human)
Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Viral myocarditis - Homo sapiens (human)
p53 signaling pathway - Homo sapiens (human)

Biological Process

mitochondrial electron transport, ubiquinol to cytochrome c
mitochondrial electron transport, cytochrome c to oxygen
protein dephosphorylation
mitochondrion organization
activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c

Molecular Function

protein serine/threonine phosphatase activity
protein binding
heme binding
electron transporter, transferring electrons from CoQH2-cytochrome c reductase complex and cytochrome c oxidase complex activity
metal ion binding

Cellular Component

protein phosphatase type 2A complex
nucleus
mitochondrion
mitochondrial inner membrane
mitochondrial intermembrane space

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000305786
Coding exons: 2
Length: 5271
Individuals with no LoFs: 125640
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125641
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.18	30	54.6	0.549	0.00000277	692
Missense (PolyPhen)		0	5.4301	0		81
Synonymous	-1.07	26	19.9	1.31	0.00000113	187
Loss of Function	1.67	0	3.25	0.00	1.38e-7	51

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Electron carrier protein. The oxidized form of the cytochrome c heme group can accept an electron from the heme group of the cytochrome c1 subunit of cytochrome reductase. Cytochrome c then transfers this electron to the cytochrome oxidase complex, the final protein carrier in the mitochondrial electron-transport chain.;
Disease: DISEASE: Thrombocytopenia 4 (THC4) [MIM:612004]: Thrombocytopenia is defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting. {ECO:0000269|PubMed:18345000}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.988

Intolerance Scores

RVIS EVS: 0.08
RVIS percentile EVS: 59.43

Essentials

Essential (CRISPR): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.998

Gene Damage Prediction

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