SLC4A10

protein-coding

solute carrier family 4 member 10, the group of Solute carrier family 4

Gene summary

This gene belongs to a small family of sodium-coupled bicarbonate transporters (NCBTs) that regulate the intracellular pH of neurons, the secretion of bicarbonate ions across the choroid plexus, and the pH of the brain extracellular fluid. The protein encoded by this gene was initially identified as a sodium-driven chloride bicarbonate exchanger (NCBE) though there is now evidence that its sodium/bicarbonate cotransport activity is independent of any chloride ion countertransport under physiological conditions. This gene is now classified as a member A10 of the SLC4 family of transmembrane solute carriers. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, May 2010]

MANE transcript

NM_001178015.2

Inheritance

ClinVar variants

P:12U:116B:19

Top phenotype

Neurodevelopmental disorder with hypotonia and characteristic brain abnormalities

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr2:161,424,332-161,985,282

External References & Databases

Ensembl (ENSG00000144290)

Transcript & Mutation Effects

hg38 • Region Span ~561.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with hypotonia and characteristic brain abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0958278

Submitter: PanelApp Australia

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

*SLC4A10* encodes a plasma membrane-bound transporter that mediates sodium-dependent bicarbonate import. This gene is highly expressed in the brain and regulates pH in neuronal cells. *SLC4A10* was first reported with autosomal recessive complex neurodevelopmental disorder in 2023 (Fasham et al., PMID: 37459438). Most reported individuals have microcephaly, developmental delay/intellectual disability, and abnormal findings on brain MRI. A few have seizures. This curation includes one multi-exon deletion, one splicing, 2 nonsense, and seven missense variants (two composing a haplotype) reported in nine probands and eight affected siblings across two publications (PMIDs: 37459438 and 38054405). For the missense variants, the location of the altered protein within the cell and acid extrusion function were tested with the majority performing similarly to a null variant (PMID: 38054405). The mechanism of pathogenicity appears to be loss of function. An animal model also supports this gene-disease relationship (PMIDs: 18165320 and 37459438). In summary, there is strong evidence to support the relationship between *SLC4A10* and autosomal recessive complex neurodevelopmental disorder. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on December 17, 2024 (SOP version 11).

neurodevelopmental disorder with hypotonia and characteristic brain abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0958278

Submitter: Baylor College of Medicine Research Center

neurodevelopmental disorder with hypotonia and characteristic brain abnormalitiesMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0958278

Submitter: G2P

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with hypotonia and characteristic brain abnormalitiesAR

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 37459438; 38054405

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC4A10 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 87

not providedTotal: 43

Neurodevelopmental disorder with hypotonia and characteristic brain abnormalitiesTotal: 13

not specifiedTotal: 9

SLC4A10-related disorderTotal: 8

SLC4A10-related neurodevelopmental disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001178015.2. 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	14 clinvar	3 clinvar	18
missense	5 clinvar		111 clinvar	2 clinvar		118
nonsense	1 clinvar	2 clinvar	3 clinvar			6
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)		3 clinvar	1 clinvar			4
Total	6	6	116	16	3	147

Highest pathogenic variant AF is 0.000014427173

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001178015.2	RefSeq	NP_001171486.1	26	MANE Select
ENST00000446997.6	Ensembl	ENSP00000393066.1	26	MANE Select
NM_001178016.2	RefSeq	NP_001171487.1	25	Standard
NM_001354440.2	RefSeq	NP_001341369.1	26	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miR-targeted genes in epithelium - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase
miR-targeted genes in squamous cell - TarBase
Transport of inorganic cations/anions and amino acids/oligopeptides

Biological Process

sodium ion transport
chloride transport
response to light stimulus
post-embryonic development
bicarbonate transport

Molecular Function

inorganic anion exchanger activity
sodium:bicarbonate symporter activity
anion:anion antiporter activity

Cellular Component

plasma membrane
integral component of plasma membrane
integral component of membrane
basolateral plasma membrane
neuronal cell body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000446997
Coding exons: 26
Length: 560950
Individuals with no LoFs: 125435
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125464
p: 0.000116

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.84	312	570	0.548	0.0000283	7291
Missense (PolyPhen)		100	314.12	0.31835		4005
Synonymous	0.163	197	200	0.985	0.0000101	2120
Loss of Function	5.38	14	58.3	0.240	0.00000303	730

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000063	rare
Latino/Admixed American	0.00047	0.00046	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.00024	0.00023	rare
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0.000073	0.000065	rare
Other	0.00018	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Electrogenic sodium/bicarbonate cotransporter in exchange for intracellular chloride. Plays an important role in regulating intracellular pH (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.118

Intolerance Scores

LoFtool: 0.770
RVIS EVS: -0.84
RVIS percentile EVS: 11.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.232

Gene Damage Prediction

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