SLC30A2
protein-codingsolute carrier family 30 member 2, the group of Solute carrier family 30
Gene summary
The protein encoded by this gene is a zinc transporter that acts as a homodimer. The encoded protein plays a role in secreting zinc into breast milk. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]
- ZNT2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~8.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0011973
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011973
Submitter: ClinGen
The SLC30A2 gene, encoding zinc transporter 2 (ZnT2), plays a crucial role in zinc transport from secretory vesicles into breast milk in mammary gland epithelial cells via the JAK2/STAT5 pathway (PMID: 19496757, 19494234). SLC30A2 was first reported in relation to transient neonatal zinc deficiency (TNZD) in 2006 (Chowanadisai et al., PMID: 17065149). Affected infants are exclusively breastfed. Clinical manifestations include low serum zinc, skin lesions, dermatitis, erythema, alopecia, diarrhea, and failure to thrive, resembling acrodermatitis enteropathica (AE). Zinc supplements resolve symptoms without relapse after weaning. TNZD exhibits incomplete penetrance and variable expressivity, with some exclusively breastfed infants showing mild or no symptoms (PMID: 22733820). The condition typically follows an autosomal dominant inheritance pattern, though compound heterozygous and homozygous variants have been reported in mothers of early-onset TNZD infants (PMID: 23741301, 32278324). Eleven unique variants, including missense, nonsense, and frameshift mutations, documented in 13 unrelated mothers whose infants affected with TNZD across 10 publications (PMIDs: 17065149, 36967740, 22733820, 24194756, 24456035, 27304099, 28111782, 37082517, 23741301, 32278324) are included in this curation. The pathogenic mechanism involves loss-of-function through haploinsufficiency or dominant negative effects. Experimental evidence further supports this gene-disease association. Knockout (KO) mice studies revealed higher cytoplasmic zinc levels in mammary gland cells compare to wildtype (WT) littermates, with altered zinc localization and accumulation (PMID: 25851903). These results are consistent with in vitro knockdown studies using siRNA in HC11 cells demonstrating cytoplasmic zinc trapping. In addition, ZnT2 null mice demonstrated reduction in milk zinc concentration and significantly lower litter survival (PMID: 25851903). Experimental studies on the TNZD associated variants including p.His54Arg, p.Gly87Arg, p.Gly280Arg, p.Thr312Met, p.Glu355Gln, p.Asp227Asn, p.Glu88Lys, p.Trp152Arg and p.Ser296Leu demonstrated various functional alterations including reduced zinc transport activity and secretion, zinc retention and mislocalization, decreased protein stability, and impaired dimerization in cell models (PMID: 17065149, 36967740, 22733820, 27137936, 23741301, 32278324). In addition, the c.838G>A p.Gly280Arg variant demonstrated aberrant splicing efficiency (PMID: 27304099). In summary, there is definitive evidence to support the relationship between autosomal dominant loss of function variants in SLC30A2 and TNZD. This classification was approved by the ClinGen IEM GCEP on January 24, 2025 (SOP Version 11).
Clinical Genomic Database (CGD)
Manifestation: Biochemical
Intervention: Biochemical
Rationale: Infants born to mothers with causative variants can show signs of zinc deficiency, and awareness may allow zinc supplementation in the infant's diet
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SLC30A2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001004434.3. 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 | 5 | 5 | ||||
| missense | 1 | 49 | 1 | 1 | 52 | |
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 1 | 1 | 2 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 3 | 2 | 50 | 6 | 1 | 62 |
Highest pathogenic variant AF is 0.00001094511
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001004434.1 | 8 | MANE Select | |
| Ensembl | ENSP00000363394.3 | 8 | MANE Select | |
| RefSeq | NP_115902.1 | 7 | Standard | |
| Ensembl | ENSP00000363396.3 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Zinc homeostasis
- Transport of bile salts and organic acids, metal ions and amine compounds
- SLC-mediated transmembrane transport
- Transport of small molecules
- Metal ion SLC transporters
Biological Process
- response to zinc ion
- regulation of sequestering of zinc ion
- positive regulation of sequestering of zinc ion
- zinc ion transmembrane transport
Molecular Function
- zinc ion transmembrane transporter activity
- protein binding
Cellular Component
- cytoplasm
- lysosomal membrane
- late endosome
- plasma membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000374276
- Coding exons
- 8
- Length
- 8882
- Individuals with no LoFs
- 125737
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 11
- Defined
- 125748
- p
- 0.0000437
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.928 | 185 | 224 | 0.826 | 0.0000125 | 2421 |
| Missense (PolyPhen) | 58 | 89.66 | 0.64689 | 1031 | ||
| Synonymous | 0.231 | 94 | 96.9 | 0.970 | 0.00000604 | 762 |
| Loss of Function | 2.71 | 5 | 17.1 | 0.292 | 8.68e-7 | 181 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000062 | 0.000062 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Disease
- DISEASE: Zinc deficiency, transient neonatal (TNZD) [MIM:608118]: A disorder occurring in breast-fed infants as a consequence of low milk zinc concentration in their nursing mothers, which cannot be corrected by maternal zinc supplementation. A large amount of zinc, an essential trace mineral, is required for normal growth particularly in infants, and breast milk normally contains adequate zinc to meet the requirement for infants up to 4 to 6 months of age. Zinc deficiency can lead to dermatitis, alopecia, decreased growth, and impaired immune function. The disorder shows autosomal dominant inheritance with incomplete penetrance. {ECO:0000269|PubMed:17065149, ECO:0000269|PubMed:22733820}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.159
Intolerance Scores
- LoFtool
- 0.409
- RVIS EVS
- 0.11
- RVIS percentile EVS
- 61.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.237
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |