SLC9A6

protein-coding

solute carrier family 9 member A6, the group of Solute carrier family 9

Gene summary

This gene encodes a sodium-hydrogen exchanger that is amember of the solute carrier family 9. The encoded protein localizes to early and recycling endosomes and may be involved in regulating endosomal pH and volume. Defects in this gene are associated with X-linked syndromic cognitive disability, Christianson type. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

MANE transcript

NM_001379110.1

Inheritance

ClinVar variants

P:65U:354B:148

Top phenotype

Intellectual developmental disorder, X-linked syndromic, Christianson type

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chrX:135,973,841-136,047,269

External References & Databases

Ensembl (ENSG00000198689)

Transcript & Mutation Effects

hg38 • Region Span ~73.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Christianson syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010278

Submitter: PanelApp Australia

Christianson syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010278

Submitter: ClinGen

The SLC9A6 gene has been associated with a rare X-linked intellectual disability syndrome known as Christianson syndrome. Clinical features of Christianson syndrome include microcephaly, profound intellectual impairment, global developmental delay, early-onset seizures, absent speech, craniofacial dysmorphism, and hyperkinesis. Christianson syndrome primarily affects hemizygous males, but heterozygous females can be mildly affected (Sinajon et al 2016). The mechanism of disease is loss of function. Missense and truncating variants in the SLC9A6 gene have been reported in Christianson syndrome patients, and variants have either arisen de novo or been inherited from a mildly affected mother. Two distinct mouse models lacking the SLC9A6 gene have had phenotypic features consistent with Christianson syndrome (Ouyang et al 2013, Xu et al 2017). In summary, SLC9A6 is definitively associated with Christianson syndrome in an X-linked manner. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. More information can be found at GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK475801/)

Christianson syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010278

Submitter: Orphanet

Christianson syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010278

Submitter: G2P

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked syndromic, Christianson typeXL

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

Comments: In addition to other features, retinitis pigmentosa has been described

Refs: 10528855; 18342287; 19377476; 20949524; 22931061; 25044251

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC9A6 variants in ClinVar

28 Conditions Cataloged

Christianson syndromeTotal: 443

not providedTotal: 206

not specifiedTotal: 67

Inborn genetic diseasesTotal: 50

SLC9A6-related disorderTotal: 20

Intellectual disabilityTotal: 8

SeizureTotal: 2

Neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairmentTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001379110.1. 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			26 clinvar	112 clinvar	7 clinvar	145
missense	1 clinvar	10 clinvar	286 clinvar	23 clinvar	4 clinvar	324
nonsense	9 clinvar	4 clinvar	12 clinvar			25
start loss						0
frameshift	17 clinvar	8 clinvar	3 clinvar			28
splice donor/acceptor (+/-2bp)	7 clinvar	9 clinvar	27 clinvar	2 clinvar		45
Total	34	31	354	137	11	567

Highest pathogenic variant AF is 0.0000053630088

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001379110.1	RefSeq	NP_001366039.1	17	MANE Select
ENST00000630721.3	Ensembl	ENSP00000487486.2	17	MANE Select
NM_001042537.2	RefSeq	NP_001036002.1	16	Standard
NM_001177651.2	RefSeq	NP_001171122.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cardiac muscle contraction - Homo sapiens (human)
Beta-agonist/Beta-blocker Pathway, Pharmacodynamics
Sodium/Proton exchangers
Transport of inorganic cations/anions and amino acids/oligopeptides
SLC-mediated transmembrane transport

Biological Process

ion transport
brain-derived neurotrophic factor receptor signaling pathway
axon extension
neuron projection morphogenesis
synapse organization

Molecular Function

sodium:proton antiporter activity
potassium:proton antiporter activity

Cellular Component

mitochondrion
late endosome
endoplasmic reticulum membrane
plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000370695
Coding exons: 16
Length: 61826
Individuals with no LoFs: 125611
Homozygous LoFs: 1
Heterozygous LoFs: 0
Defined: 125612
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.95	137	275	0.499	0.0000202	4591
Missense (PolyPhen)		33	123.01	0.26827		2116
Synonymous	0.359	100	105	0.955	0.00000791	1406
Loss of Function	4.26	1	23.1	0.0434	0.00000171	379

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)	0.000012	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Electroneutral exchange of protons for Na(+) and K(+) across the early and recycling endosome membranes. Contributes to calcium homeostasis.;

Recessive Scores

pRec: 0.112

Intolerance Scores

RVIS EVS: -0.18
RVIS percentile EVS: 39.95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.657

Gene Damage Prediction

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