SLC6A2

protein-coding

solute carrier family 6 member 2, the group of Solute carrier family 6

Gene summary

This gene encodes a member of the sodium:neurotransmitter symporter family. This member is a multi-pass membrane protein, which is responsible for reuptake of norepinephrine into presynaptic nerve terminals and is a regulator of norepinephrine homeostasis. Mutations in this gene cause orthostatic intolerance, a syndrome characterized by lightheadedness, fatigue, altered mentation and syncope. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene.[provided by RefSeq, Feb 2010]

Previous symbols:

NET1
NAT1
SLC6A5

MANE transcript

NM_001172501.3

Inheritance

ClinVar variants

P:1U:63B:26

Top phenotype

Orthostatic intolerance

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr16:55,655,988-55,707,645

External References & Databases

Ensembl (ENSG00000103546)

Transcript & Mutation Effects

hg38 • Region Span ~51.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

postural orthostatic tachycardia syndrome due to NET deficiencySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011479

Submitter: Orphanet

postural orthostatic tachycardia syndrome due to NET deficiencyLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0011479

Submitter: Labcorp Genetics (formerly Invitae)

postural orthostatic tachycardia syndrome due to NET deficiencyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011479

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Orthostatic intoleranceAD

Manifestation: Endocrine; 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: 10684912; 11458707; 12805287

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC6A2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 65

not providedTotal: 28

SLC6A2-related disorderTotal: 6

Neurocirculatory astheniaTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001172501.3. 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				13 clinvar	4 clinvar	17
missense	1 clinvar		63 clinvar	6 clinvar	3 clinvar	73
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	1	0	63	19	7	90

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001172501.3	RefSeq	NP_001165972.1	14	MANE Select
ENST00000568943.6	Ensembl	ENSP00000457473.1	14	MANE Select
NM_001043.3	RefSeq	NP_001034.1	14	Standard
NM_001172502.1	RefSeq	NP_001165973.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Venlafaxine Pathway, Pharmacokinetics
Sympathetic Nerve Pathway (Neuroeffector Junction)
Levomethadyl Acetate Action Action Pathway
Fluoxetine Action Pathway
Citalopram Action Pathway

Biological Process

chemical synaptic transmission
monoamine transport
norepinephrine transport
response to pain
dopamine uptake involved in synaptic transmission

Molecular Function

actin binding
neurotransmitter:sodium symporter activity
dopamine:sodium symporter activity
norepinephrine:sodium symporter activity
protein binding

Cellular Component

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

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000219833
Coding exons: 14
Length: 50589
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 19
Defined: 125748
p: 0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.02	254	362	0.701	0.0000218	4094
Missense (PolyPhen)		89	152.26	0.58454		1750
Synonymous	-1.56	188	163	1.16	0.0000116	1270
Loss of Function	3.76	8	30.4	0.264	0.00000142	344

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00025	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals. {ECO:0000269|PubMed:2008212}.;
Disease: DISEASE: Orthostatic intolerance (OI) [MIM:604715]: Syndrome characterized by lightheadedness, fatigue, altered mentation and syncope. It is associated with postural tachycardia. Plasma norepinephrine concentration is abnormally high. {ECO:0000269|PubMed:10684912}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.252

Intolerance Scores

LoFtool: 0.538
RVIS EVS: -0.44
RVIS percentile EVS: 24.46

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.187

Gene Damage Prediction

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