rs6351

Variant names:

• chr5-1443036-G-A
• rs6351
• NM_001044.5:c.162C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1443036-G-A
• chr5-1443036-G-C
• chr5-1443036-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001044.5(SLC6A3):​c.162C>T​(p.Pro54Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,186 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P54P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (6 hom., cov: 33)
  • Exomes 𝑓: 0.011 (105 hom.)
• Consequence: SLC6A3 NM_001044.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.268
• Publications: 9 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Ambry Genetics
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-1443036-G-A is Benign according to our data. Variant chr5-1443036-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 470636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.268 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00638 (971/152296) while in subpopulation NFE AF = 0.0109 (742/68012). AF 95% confidence interval is 0.0103. There are 6 homozygotes in GnomAd4. There are 455 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.162C>T	p.Pro54Pro	synonymous	Exon 2 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.162C>T	p.Pro54Pro	synonymous	Exon 2 of 15	ENSP00000270349.9	Q01959
	SLC6A3	ENST00000941790.1		c.162C>T	p.Pro54Pro	synonymous	Exon 2 of 14	ENSP00000611849.1
	SLC6A3	ENST00000713696.1		c.162C>T	p.Pro54Pro	synonymous	Exon 2 of 15	ENSP00000519000.1	A0AAQ5BGN6

Frequencies

GnomAD3 genomes AF: 0.00639 AC: 972 AN: 152178 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00704 AC: 1769 AN: 251378 AF XY: 0.00761

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00103

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.0107 AC: 15663 AN: 1461890 Hom.: 105 Cov.: 33 AF XY: 0.0107 AC XY: 7772 AN XY: 727244

African (AFR) AF: 0.00122 AC: 41 AN: 33480

American (AMR) AF: 0.00356 AC: 159 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26136

East Asian (EAS) AF: 0.00262 AC: 104 AN: 39700

South Asian (SAS) AF: 0.00988 AC: 852 AN: 86258

European-Finnish (FIN) AF: 0.00477 AC: 255 AN: 53418

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.0122 AC: 13610 AN: 1112010

Other (OTH) AF: 0.00950 AC: 574 AN: 60396

GnomAD4 genome AF: 0.00638 AC: 971 AN: 152296 Hom.: 6 Cov.: 33 AF XY: 0.00611 AC XY: 455 AN XY: 74478

African (AFR) AF: 0.00192 AC: 80 AN: 41562

American (AMR) AF: 0.00399 AC: 61 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.00766 AC: 37 AN: 4832

European-Finnish (FIN) AF: 0.00301 AC: 32 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0109 AC: 742 AN: 68012

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00818 Hom.: 8

Bravo AF: 0.00656

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.0102

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Classic dopamine transporter deficiency syndrome (2)
-	-	1	Parkinsonism-dystonia, infantile (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.59
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs6351; hg19: chr5-1443151;