GeneBe

CISD2

protein-coding

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

Gene summary

The protein encoded by this gene is a zinc finger protein that localizes to the endoplasmic reticulum. The encoded protein binds an iron/sulfur cluster and may be involved in calcium homeostasis. Defects in this gene are a cause of Wolfram syndrome 2. [provided by RefSeq, Mar 2011]

Previous symbols:
  • ZCD2
  • WFS2

MANE transcript

NM_001008388.5

Inheritance

AR

ClinVar variants

P:3U:36B:27

Top phenotype

Wolfram syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr4:102,868,974-102,892,807

External References & Databases

Ensembl (ENSG00000145354)NCBI Gene (493856)OMIM (611507)HGNC:24212GenCCUniProt (Q8N5K1)AlphaFoldClinVar (CISD2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~23.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Wolfram syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011502

Submitter: G2P

Wolfram syndrome 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011502

Submitter: Ambry Genetics

Wolfram syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011502

Submitter: Genomics England PanelApp

Wolfram syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011502

Submitter: Labcorp Genetics (formerly Invitae)

Wolfram syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018105

Submitter: Orphanet

Wolfram syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018105

Submitter: ClinGen

The *CISD2* gene was first associated with autosomal recessive Wolfram syndrome (WFS) in 2007 (Amr et al., PMID: 17846994). At least 6 unique variants (missense, splice-site, small deletion) have been reported in 9 probands in 7 publications (PMIDs: 17846994, 25056293, 25371195, 28335035, 27459537, 31391115, 31309279). At least two families have been identified in which a variant in CISD2 segregates with WFS in 8 family members (PMID: 17846994). Three mouse models, functional alteration studies and expression studies have been reported to show that LoF of the *CISD2* gene leads to a phenotype similar to WFS or changes the behavior of the cells in which the variant protein is present (PMIDs: 19451219, 24833725, 28335035, 17846994, 31600780, 29237418. 33610659). In summary, there is definitive evidence to support the relationship between *CISD2* and autosomal recessive Wolfram syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated as Strong by the ClinGen Hearing Loss Working Group on 3/27/2018 as per SOP v6. It was reevaluated on 6/1/2023 as per SOP v9. As a result of this reevaluation, the classification increased from Strong to Definitive due to additional case level evidence (PMIDs: 27459537, 31391115, 31309279) as well as functional evidence (PMIDs: 17846994, 31600780, 29237418. 33610659).

Clinical Genomic Database (CGD)

Wolfram syndrome 2AR

Manifestation: Audiologic/Otolaryngologic; Endocrine; Gastrointestinal; Genitourinary; Hematologic; Ophthalmologic; Renal

Intervention: Gastrointestinal; Genitourinary; Hematologic; Renal

Rationale: 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

Refs: 10739754; 11317648; 12116178; 17846994; 22790102; 23429432; 25056293Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CISD2 variants in ClinVar

5 Conditions Cataloged
not providedTotal: 64
Wolfram syndrome 2Total: 23
not specifiedTotal: 16
Inborn genetic diseasesTotal: 10
CISD2-related disorderTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001008388.5. 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.

EffectPLPVUSLBBSum
synonymous
27
clinvar
 27
missense
1
clinvar
34
clinvar
 35
nonsense
1
clinvar
 1
start loss
1
clinvar
 1
frameshift
0
splice donor/acceptor (+/-2bp)
1
clinvar
1
clinvar
 2
Total213627066

Highest pathogenic variant AF is 6.891761e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001008388.5RefSeqNP_001008389.13MANE Select
ENST00000273986.10EnsemblENSP00000273986.43MANE Select
ENST00000503643.1EnsemblENSP00000423716.13Standard
ENST00000503643.2EnsemblENSP00000423716.13Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • autophagy of mitochondrion
  • multicellular organism aging
  • regulation of autophagy

Molecular Function

  • RNA binding
  • protein binding
  • protein homodimerization activity
  • metal ion binding
  • 2 iron, 2 sulfur cluster binding

Cellular Component

  • mitochondrial outer membrane
  • endoplasmic reticulum
  • endoplasmic reticulum membrane
  • membrane
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000273986
Coding exons
3
Length
20265
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.274272.40.5800.00000398870
Missense (PolyPhen)2131.7050.66236353
Synonymous-0.6593227.61.160.00000145266
Loss of Function1.7115.200.1922.19e-767

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

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

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.181

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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