SLC30A5

protein-coding

solute carrier family 30 member 5, the group of Solute carrier family 30

Gene summary

This gene encodes a member of the SLC30A/ZnT family of zinc transporter proteins. ZnT proteins mediate both cellular zinc efflux and zinc sequestration into membrane-bound organelles. The encoded protein plays a role in the early secretory pathway as a heterodimer with zinc transporter 6, and may also regulate zinc sequestration into secretory granules of pancreatic beta cells. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 19. [provided by RefSeq, Oct 2011]

MANE transcript

NM_022902.5

Inheritance

ClinVar variants

P:2U:78B:5

Top phenotype

Noncompaction cardiomyopathy

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr5:69,093,991-69,131,069

External References & Databases

Ensembl (ENSG00000145740)

Transcript & Mutation Effects

hg38 • Region Span ~37.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cardiomyopathyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0004994

Submitter: PanelApp Australia

dilated cardiomyopathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0005021

Submitter: Ambry Genetics

dilated cardiomyopathyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0005021

Submitter: LiferaOmics

Genetic evidence – Published PMID: 33547425 – Family 1 – one proband (affected siblings counted under segregation). Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation (affected siblings; conservative assignment) = 0.5; Case-control = 0 Family 1 total = 1.5 PMID: 33547425 – Family 2 – one proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0; Case-control = 0 Family 2 total = 1.0 Published genetic evidence total = 2.5 / 12 Genetic evidence – Our cases Family 1 – one proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0 (affected sibling not genotyped; not scored); Case-control = 0 Family 1 total = 1.0 Family 2 – one proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0 (affected sibling not genotyped; not scored); Case-control = 0 Family 2 total = 1.0 Total genetic evidence (published AR + our cases) 2.5 (published AR) + 2.0 (our case) = 4.5 / 12 Experimental evidence – Published PMID: 33547425 – Prior ZnT5 knockout mouse data demonstrate significant mortality due to cardiac arrhythmia/bradyarrhythmia, supporting a mechanistic link between SLC30A5 loss-of-function and severe cardiac phenotype. Model system evidence = 1.0 SLC30A5 (ZnT5) biology – SLC30A5 encodes a zinc transporter localized to ER/Golgi membranes, essential for intracellular zinc homeostasis. This supports biological plausibility that loss-of-function could disrupt cardiac development and function. Gene function / biological plausibility = 1.0 PMID: 12095919 experimental/model evidence It studies Znt5 = SLC30A5 (ortholog) Knockout mice show: Premature/sudden cardiac death experimental/model evidence =0.5 Experimental evidence total = 2 / 6 Overall score Genetic evidence = 4.5 Experimental evidence = 2.5 Overall score = 7 / 18

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC30A5 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 74

not providedTotal: 5

Noncompaction cardiomyopathyTotal: 2

Concentric hypertrophic cardiomyopathyTotal: 2

Hypertrophic cardiomyopathyTotal: 2

Hydrops fetalisTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022902.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar		2 clinvar	4
missense			72 clinvar	2 clinvar	1 clinvar	75
nonsense			1 clinvar			1
start loss						0
frameshift		2 clinvar	1 clinvar			3
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	2	78	2	3	85

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 53 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022902.5	RefSeq	NP_075053.2	16	MANE Select
ENST00000396591.8	Ensembl	ENSP00000379836.3	16	MANE Select
NM_001251969.2	RefSeq	NP_001238898.1	3	Standard
NM_024055.5	RefSeq	NP_076960.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Zinc homeostasis
Peptide hormone metabolism
Metabolism of proteins
Transport of bile salts and organic acids, metal ions and amine compounds
SLC-mediated transmembrane transport

Biological Process

cobalt ion transport
zinc ion transport
cellular zinc ion homeostasis
response to zinc ion
regulation of proton transport

Molecular Function

zinc ion transmembrane transporter activity
zinc ion binding

Cellular Component

nucleus
nucleolus
Golgi apparatus
integral component of plasma membrane
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396591
Coding exons: 16
Length: 37424
Individuals with no LoFs: 125708
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125747
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.01	281	393	0.714	0.0000189	5016
Missense (PolyPhen)		42	90.909	0.462		1153
Synonymous	0.972	124	139	0.895	0.00000720	1499
Loss of Function	4.00	9	34.2	0.263	0.00000172	431

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000062	0.000058	rare
Ashkenazi Jewish	0.00035	0.00030	rare
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.000042	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions as a zinc transporter. May be a transporter of zinc into beta cells in order to form insulin crystals. Partly regulates cellular zinc homeostasis. Required with ZNT7 for the activation of zinc-requiring enzymes, alkaline phosphatases (ALPs). Transports zinc into the lumens of the Golgi apparatus and vesicular compartments where ALPs locate, thus, converting apoALPs to holoALPs. Required with ZNT6 and ZNT7 for the activation of TNAP. {ECO:0000269|PubMed:11904301, ECO:0000269|PubMed:11937503, ECO:0000269|PubMed:15276077, ECO:0000269|PubMed:15525635, ECO:0000269|PubMed:15994300}.;

Recessive Scores

pRec: 0.132

Intolerance Scores

LoFtool: 0.592
RVIS EVS: -0.09
RVIS percentile EVS: 47.06

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.320

Gene Damage Prediction

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