CISD2

CDGSH iron sulfur domain 2, the group of CDGSH iron sulfur domain containing

Basic information

Region (hg38): 4:102868973-102892807

Previous symbols: [ "ZCD2", "WFS2" ]

Links

ENSG00000145354 ∙ NCBI:493856 ∙ OMIM:611507 ∙ HGNC:24212 ∙ Uniprot:Q8N5K1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Wolfram syndrome 2 (Strong), mode of inheritance: AR
• Wolfram syndrome 2 (Strong), mode of inheritance: AR
• Wolfram syndrome 2 (Strong), mode of inheritance: AR
• Wolfram syndrome 2 (Moderate), mode of inheritance: AR
• Wolfram syndrome (Supportive), mode of inheritance: AR
• Wolfram syndrome 2 (Strong), mode of inheritance: AR
• Wolfram syndrome (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Wolfram syndrome 2	AR	Gastrointestinal; Genitourinary; Hematologic; Renal	Urinary tract anomalies can lead to severe (and potentially avoidable) renal sequelae, including renal failure, and surveillance and early management can be beneficial; Surveillance for and early treatment of bleeding diatheses (as well as related GI disease that can lead to bleeding) can be beneficial	Audiologic/Otolaryngologic; Endocrine; Gastrointestinal; Genitourinary; Hematologic; Ophthalmologic; Renal	10739754; 11317648; 12116178; 17846994; 22790102; 23429432; 25056293

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CISD2 gene.

• not provided (46 variants)
• Wolfram syndrome 2 (8 variants)
• not specified (3 variants)
• Inborn genetic diseases (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CISD2 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				16		16
missense			16			16
nonsense						0
start loss			1			1
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			2			2
non coding				13	1	14
Total	0	0	17	29	1

Variants in CISD2

This is a list of pathogenic ClinVar variants found in the CISD2 region.

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

Position	Type	Phenotype	Significance	ClinVar
4-102869053-G-A		not specified	Likely benign (Dec 15, 2017)
4-102869087-G-A		Wolfram syndrome 2	Uncertain significance (Sep 01, 2022)
4-102869094-G-C		Inborn genetic diseases	Uncertain significance (Jul 20, 2021)
4-102869096-G-A		CISD2-related disorder	Conflicting classifications of pathogenicity (Jan 15, 2024)
4-102869103-G-A			Uncertain significance (Jul 06, 2022)
4-102869105-C-T			Likely benign (Sep 10, 2023)
4-102869132-A-C			Likely benign (Jan 18, 2024)
4-102869136-C-T			Likely benign (Jan 31, 2024)
4-102869144-G-C		Wolfram syndrome 2	Benign/Likely benign (Dec 23, 2023)
4-102869167-C-T		Wolfram syndrome 2	Uncertain significance (Jul 10, 2023)
4-102869168-C-G			Likely benign (Jun 15, 2022)
4-102869176-C-T			Uncertain significance (Nov 04, 2020)
4-102869188-G-A		Wolfram syndrome 2	Pathogenic (Jul 30, 2019)
4-102869192-T-G		CISD2-related disorder	Conflicting classifications of pathogenicity (Apr 12, 2022)
4-102869193-C-A		Wolfram syndrome 2	Uncertain significance (Feb 05, 2022)
4-102869196-C-T			Likely benign (Aug 04, 2023)
4-102869199-C-G			Likely benign (Jun 29, 2023)
4-102869199-C-T			Likely benign (Jan 02, 2022)
4-102869200-C-T			Likely benign (Sep 15, 2023)
4-102869201-A-C			Likely benign (Jan 31, 2023)
4-102869203-C-G			Likely benign (Jul 19, 2023)
4-102874540-C-G			Likely benign (May 01, 2023)
4-102885206-A-G			Likely benign (Jul 25, 2022)
4-102885207-C-A		Wolfram syndrome 2 • CISD2-related disorder	Benign/Likely benign (Dec 12, 2023)
4-102885221-G-C		Wolfram syndrome 2	Pathogenic (Oct 01, 2007)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CISD2	protein_coding	protein_coding	ENST00000273986	3	20265

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.416	0.552	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.27	42	72.4	0.580	0.00000398	870
Missense in Polyphen		21	31.705	0.66236		353
Synonymous	-0.659	32	27.6	1.16	0.00000145	266
Loss of Function	1.71	1	5.20	0.192	2.19e-7	67

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Regulator of autophagy that contributes to antagonize BECN1-mediated cellular autophagy at the endoplasmic reticulum. Participates in the interaction of BCL2 with BECN1 and is required for BCL2-mediated depression of endoplasmic reticulum Ca(2+) stores during autophagy. Contributes to BIK-initiated autophagy, while it is not involved in BIK-dependent activation of caspases. Involved in life span control, probably via its function as regulator of autophagy. {ECO:0000269|PubMed:17846994, ECO:0000269|PubMed:20010695}.

Recessive Scores

• pRec: 0.110

Intolerance Scores

• loftool: 0.215
• rvis_EVS: -0.05
• rvis_percentile_EVS: 49.39

Haploinsufficiency Scores

• pHI: 0.186
• hipred: Y
• hipred_score: 0.545
• ghis: 0.556

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.181

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cisd2
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; muscle phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; skeleton phenotype; renal/urinary system phenotype; vision/eye phenotype; hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; pigmentation phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype

Gene ontology

• Biological process: autophagy of mitochondrion;multicellular organism aging;regulation of autophagy
• Cellular component: mitochondrial outer membrane;endoplasmic reticulum;endoplasmic reticulum membrane;membrane;integral component of membrane;protein-containing complex;perinuclear endoplasmic reticulum
• Molecular function: RNA binding;protein binding;protein homodimerization activity;metal ion binding;2 iron, 2 sulfur cluster binding