SLC6A3 p.Asn466Lys

Variant names:

• chr5-1409721-G-T
• NM_001044.5:c.1398C>A
• SLC6A3 p.Asn466Lys

Your query was ambiguous. Multiple possible variants found:

• chr5-1409721-G-T
• chr5-1409721-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001044.5(SLC6A3):​c.1398C>A​(p.Asn466Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N466N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC6A3 NM_001044.5 missense, splice_region
• Scores: Splicing: ADA: 0.00003635
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0990
• Publications: 0 publications found

Genes affected

SLC6A3 (HGNC:11049): (solute carrier family 6 member 3) This gene encodes a dopamine transporter which is a member of the sodium- and chloride-dependent neurotransmitter transporter family. The 3' UTR of this gene contains a 40 bp tandem repeat, referred to as a variable number tandem repeat or VNTR, which can be present in 3 to 11 copies. Variation in the number of repeats is associated with idiopathic epilepsy, attention-deficit hyperactivity disorder, dependence on alcohol and cocaine, susceptibility to Parkinson disease and protection against nicotine dependence.[provided by RefSeq, Nov 2009]

SLC6A3 Gene-Disease associations (from GenCC):

• classic dopamine transporter deficiency syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• SLC6A3-related dopamine transporter deficiency syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• parkinsonism-dystonia, infantile

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001044.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A3	NM_001044.5	MANE Select	c.1398C>A	p.Asn466Lys	missense splice_region	Exon 10 of 15	NP_001035.1	Q01959

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A3	ENST00000270349.12	TSL:1 MANE Select	c.1398C>A	p.Asn466Lys	missense splice_region	Exon 10 of 15	ENSP00000270349.9	Q01959
	SLC6A3	ENST00000941790.1		c.1263C>A	p.Asn421Lys	missense splice_region	Exon 9 of 14	ENSP00000611849.1
	SLC6A3	ENST00000713696.1		c.1263C>A	p.Asn421Lys	missense splice_region	Exon 9 of 15	ENSP00000519000.1	A0AAQ5BGN6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	4.5
DANN	Benign	0.67
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.39	T
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.099
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.18
Sift	Benign	0.33	T
Sift4G	Benign	0.36	T
Varity_R		0.28
gMVP		0.79
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.024
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-1409836;