rs2550936

Variant names:

• chr5-1411141-A-C
• rs2550936
• NM_001044.5:c.1269+102T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001044.5(SLC6A3):​c.1269+102T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 810,430 control chromosomes in the GnomAD database, including 38,938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (13247 hom., cov: 32)
  • Exomes 𝑓: 0.26 (25691 hom.)
• Consequence: SLC6A3 NM_001044.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.08
• 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), Ambry Genetics, G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 5-1411141-A-C is Benign according to our data. Variant chr5-1411141-A-C is described in ClinVar as Benign. ClinVar VariationId is 1180279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5	c.1269+102T>G		intron_variant	Intron 9 of 14	ENST00000270349.12	NP_001035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A3	ENST00000270349.12	c.1269+102T>G		intron_variant	Intron 9 of 14	1	NM_001044.5	ENSP00000270349.9
SLC6A3	ENST00000713696.1	c.1134+102T>G		intron_variant	Intron 8 of 14			ENSP00000519000.1
SLC6A3	ENST00000713697.1	n.*141-1292T>G		intron_variant	Intron 9 of 10			ENSP00000519001.1

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56111 AN: 151852 Hom.: 13208 Cov.: 32

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.327

GnomAD4 exome AF: 0.265 AC: 174172 AN: 658460 Hom.: 25691 AF XY: 0.262 AC XY: 91435 AN XY: 349108

African (AFR) AF: 0.685 AC: 12157 AN: 17750

American (AMR) AF: 0.166 AC: 5765 AN: 34758

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 5837 AN: 20644

East Asian (EAS) AF: 0.101 AC: 3263 AN: 32454

South Asian (SAS) AF: 0.236 AC: 15286 AN: 64756

European-Finnish (FIN) AF: 0.241 AC: 9348 AN: 38788

Middle Eastern (MID) AF: 0.284 AC: 1126 AN: 3962

European-Non Finnish (NFE) AF: 0.272 AC: 111787 AN: 411498

Other (OTH) AF: 0.284 AC: 9603 AN: 33850

GnomAD4 genome AF: 0.370 AC: 56201 AN: 151970 Hom.: 13247 Cov.: 32 AF XY: 0.361 AC XY: 26800 AN XY: 74274

African (AFR) AF: 0.678 AC: 28100 AN: 41450

American (AMR) AF: 0.225 AC: 3435 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 961 AN: 3466

East Asian (EAS) AF: 0.117 AC: 603 AN: 5160

South Asian (SAS) AF: 0.248 AC: 1193 AN: 4808

European-Finnish (FIN) AF: 0.235 AC: 2489 AN: 10580

Middle Eastern (MID) AF: 0.312 AC: 91 AN: 292

European-Non Finnish (NFE) AF: 0.270 AC: 18365 AN: 67908

Other (OTH) AF: 0.322 AC: 680 AN: 2110

Alfa AF: 0.331 Hom.: 1277

Bravo AF: 0.382

Asia WGS AF: 0.205 AC: 714 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.083
DANN	Benign	0.43
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2550936; hg19: chr5-1411256;