GeneBe

SLC4A2

protein-coding

solute carrier family 4 member 2, the group of Solute carrier family 4

Gene summary

This gene encodes a member of the anion exchanger family of membrane transport proteins. The encoded protein regulates intracellular pH, biliary bicarbonate secretion, and chloride uptake. Reduced expression of this gene may be associated with primary biliary cirrhosis (PBC) in human patients, while differential expression of this gene may be associated with malignant hepatocellular carcinoma, colon and gastric cancers. [provided by RefSeq, Nov 2016]

Previous symbols:
  • EPB3L1
  • AE2

MANE transcript

NM_003040.4

Inheritance

AR, AD

ClinVar variants

P:3U:189B:10

Top phenotype

Osteopetrosis, autosomal recessive 9

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr7:151,057,210-151,076,526

External References & Databases

Ensembl (ENSG00000164889)NCBI Gene (6522)OMIM (109280)HGNC:11028GenCCUniProt (P04920)AlphaFoldClinVar (SLC4A2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~19.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

osteopetrosis, autosomal recessive 9LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0957262

Submitter: LiferaOmics

Genetic evidence – Published PMID: 34668226 – Family 1 – one proband. Case-level (AR compound heterozygous; non-LOF start = 0.1; variants evaluated individually then combined; in-trans confirmed) = 0.6; Segregation = 0; Case-control = 0 Family 1 total = 0.6 Published genetic evidence total = 0.6 / 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; Case-control = 0 Family 1 total = 1.0 Total genetic evidence (published AR + our cases) 0.6 (published AR; PMID: 34668226) + 1.0 (our case) = 1.6 / 12 Experimental evidence – Published (conservative scoring) PMID: 34668226 – Demonstrates that SLC4A2 variants impair anion exchange activity and disrupt osteoclast differentiation and bone resorption in engineered cellular assays relevant to osteopetrosis. Functional alteration (engineered cells; disease-relevant assays) = 1.0 PMID: 19164575 – Slc4a2 (Ae2) knockout mouse model demonstrates defective osteoclast function and osteopetrosis, supporting the disease mechanism. Model system evidence (animal model; conservative assignment) = 1.0 PMID: 20507629 – Bovine osteopetrosis associated with SLC4A2 deletion further supports cross-species relevance of SLC4A2 in bone resorption. Gene function / biological plausibility = 0.5 Experimental evidence total = 2.5 / 6 Overall score Genetic evidence = 1.6 Experimental evidence = 2.5 Overall score = 4.1 / 18

osteopetrosis, autosomal recessive 9MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0957262

Submitter: PanelApp Australia

hereditary spherocytosis type 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012981

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Osteopetrosis, autosomal recessive 9AR

Manifestation: Musculoskeletal; Renal

Intervention: Renal

Rationale: An individual has been described with renal failure requiring renal transplant, and awareness may enable early diagnosis and management of renal issues and sequelae

Refs: 34668226Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC4A2 variants in ClinVar

4 Conditions Cataloged
not specifiedTotal: 158
not providedTotal: 26
Osteopetrosis, autosomal recessive 9Total: 3
Distal renal tubular acidosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003040.4. 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
12
clinvar
5
clinvar
2
clinvar
 19
missense
2
clinvar
1
clinvar
171
clinvar
3
clinvar
 177
nonsense
0
start loss
0
frameshift
1
clinvar
 1
splice donor/acceptor (+/-2bp)
5
clinvar
 5
Total2118982202

Highest pathogenic variant AF is 6.8440744e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003040.4RefSeqNP_003031.322MANE Select
ENST00000413384.7EnsemblENSP00000405600.222MANE Select
NM_001199692.3RefSeqNP_001186621.122Standard
NM_001199693.1RefSeqNP_001186622.122Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Bile secretion - Homo sapiens (human)
  • Gastric acid secretion - Homo sapiens (human)
  • Salivary secretion - Homo sapiens (human)
  • Pancreatic secretion - Homo sapiens (human)
  • Transport of inorganic cations/anions and amino acids/oligopeptides

Biological Process

  • anion transport
  • spermatogenesis
  • inorganic anion transport
  • bicarbonate transport
  • digestive tract development

Molecular Function

  • inorganic anion exchanger activity
  • anion transmembrane transporter activity
  • anion:anion antiporter activity
  • enzyme binding

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • focal adhesion
  • membrane
  • basolateral plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000485713
Coding exons
22
Length
19318
Individuals with no LoFs
125728
Homozygous LoFs
0
Heterozygous LoFs
16
Defined
125744
p
0.0000636
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.975668030.7050.00005417934
Missense (PolyPhen)193362.160.532913624
Synonymous0.5453283410.9620.00002272683
Loss of Function5.56952.50.1720.00000299550

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.0000890.000087rare
Ashkenazi Jewish00.0absent
East Asian0.0000550.000054rare
Finnish0.0000470.000046rare
European (Non-Finnish)0.0000730.000070rare
South Asian00.0absent
Other0.000350.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Plasma membrane anion exchange protein of wide distribution.;

Intolerance Scores

LoFtool
0.0699
RVIS EVS
-1.77
RVIS percentile EVS
2.32

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.454

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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