SLC30A10

protein-coding

solute carrier family 30 member 10, the group of Solute carrier family 30

Gene summary

This gene is highly expressed in the liver and is inducible by manganese. Its protein product appears to be critical in maintaining manganese levels, and has higher specificity for manganese than zinc. Loss of function mutations appear to result in a pleomorphic phenotype, including dystonia and adult-onset parkinsonism. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Mar 2012]

MANE transcript

NM_018713.3

Inheritance

ClinVar variants

P:11U:131B:83

Top phenotype

Hypermanganesemia with dystonia 1

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr1:219,685,427-219,959,018

External References & Databases

Ensembl (ENSG00000196660)

Transcript & Mutation Effects

hg38 • Region Span ~273.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cirrhosis - dystonia - polycythemia - hypermanganesemia syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013208

Submitter: PanelApp Australia

cirrhosis - dystonia - polycythemia - hypermanganesemia syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013208

Submitter: Genomics England PanelApp

cirrhosis - dystonia - polycythemia - hypermanganesemia syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013208

Submitter: Labcorp Genetics (formerly Invitae)

cirrhosis - dystonia - polycythemia - hypermanganesemia syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013208

Submitter: Orphanet

Clinical Genomic Database (CGD)

Hypermanganesemia with dystonia 1AR

Manifestation: Biochemical; Gastrointestinal; Hematologic; Neurologic

Intervention: Hematologic

Rationale: The condition can involve hypermagnesemia, with gastrointestinal, neurologic, and other sequelae, and chelation therapy has been described as beneficial in some individuals

Refs: 11040156; 18087599; 18392750; 21596707; 22341971; 22341972

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC30A10 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 193

Inborn genetic diseasesTotal: 62

Hypermanganesemia with dystonia, polycythemia, and cirrhosisTotal: 37

not specifiedTotal: 10

SLC30A10-related disorderTotal: 7

Congenital ErythrocytosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018713.3. 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			1 clinvar	75 clinvar		76
missense	1 clinvar	2 clinvar	125 clinvar	8 clinvar		136
nonsense	1 clinvar	2 clinvar	3 clinvar			6
start loss						0
frameshift	3 clinvar	2 clinvar	2 clinvar			7
splice donor/acceptor (+/-2bp)						0
Total	5	6	131	83	0	225

Highest pathogenic variant AF is 7.217538e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018713.3	RefSeq	NP_061183.2	4	MANE Select
ENST00000366926.4	Ensembl	ENSP00000355893.4	4	MANE Select
NM_001376929.1	RefSeq	NP_001363858.1	4	Standard
NM_001416004.1	RefSeq	NP_001402933.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
slc30a10	Danio rerio	Structure: nucleate erythrocyte Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

slc30a10

Danio rerio

Structure: nucleate erythrocyte

Quality: increased amount

abnormal

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

manganese ion transport
zinc ion transport
epidermal growth factor receptor signaling pathway
negative regulation of neuron apoptotic process
positive regulation of ERK1 and ERK2 cascade

Molecular Function

manganese ion transmembrane transporter activity
protein binding

Cellular Component

early endosome
Golgi apparatus
plasma membrane
integral component of membrane
recycling endosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000366926
Coding exons: 4
Length: 273221
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.58	197	270	0.730	0.0000132	3119
Missense (PolyPhen)		39	87.104	0.44774		967
Synonymous	0.130	119	121	0.985	0.00000665	1017
Loss of Function	3.20	0	11.9	0.00	5.73e-7	147

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	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a pivotal role in manganese transport. Manganese is an essential cation for the function of several enzymes, including some crucially important for the metabolism of neurotransmitters and other neuronal metabolic pathways. However, elevated levels of manganese are cytotoxic and induce oxidative stress, mitochondrial dysfunction and apoptosis. Acts as manganese efflux transporter and confers protection against manganese- induced cell death (PubMed:22341972, PubMed:22341971, PubMed:25319704, PubMed:27226609, PubMed:27307044). Also acts as zinc transporter involved in zinc homeostasis. Seems to mediate zinc transport into early endosomes and recycling endosomes to prevent zinc toxicity; the function may be regulated by heterodimerization with other zinc transporters of the SLC30A subfamily. The SLC30A3:SLC30A10 heterodimer is involved in zinc transport-dependent regulation of the EGFR/ERK transduction pathway in endosomes. May be involved in regulation of zinc- dependent senescence of vascular smooth muscle cells (PubMed:22706290, PubMed:22427991, PubMed:26728129). {ECO:0000269|PubMed:22341971, ECO:0000269|PubMed:22341972, ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:25319704, ECO:0000269|PubMed:27226609, ECO:0000305|PubMed:22706290}.;
Disease: DISEASE: Hypermanganesemia with dystonia 1 (HMNDYT1) [MIM:613280]: A metabolic autosomal recessive disorder characterized by dystonia, parkinsonism, extrapyramidal signs, severe hypermanganesemia, polycythemia, and chronic hepatic disease, including steatosis and cirrhosis. {ECO:0000269|PubMed:22341971, ECO:0000269|PubMed:22341972, ECO:0000269|PubMed:25319704}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.125

Intolerance Scores

LoFtool: 0.0689
RVIS EVS: -0.4
RVIS percentile EVS: 26.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0230

Gene Damage Prediction

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