dbSNP rs8047672: SLC6A2:c.1261-74G>A (chr16-55697823-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001172501.3(SLC6A2):c.1261-74G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,571,616 control chromosomes in the GnomAD database, including 26,358 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.19 ( 3094 hom., cov: 32)

Exomes 𝑓: 0.18 ( 23264 hom. )

Consequence

SLC6A2
NM_001172501.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.22

Publications

6 publications found

Variant links:

Genes affected

SLC6A2 (HGNC:11048): (solute carrier family 6 member 2) 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]

SLC6A2 Gene-Disease associations (from GenCC):

postural orthostatic tachycardia syndrome
Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

SLC6A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A2	NM_001172501.3 link	c.1261-74G>A		intron_variant	Intron 9 of 14	ENST00000568943.6	NP_001165972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A2	ENST00000568943.6 link	c.1261-74G>A		intron_variant	Intron 9 of 14	1	NM_001172501.3	ENSP00000457473.1

Frequencies

GnomAD3 genomes

AF:

0.192

AC:

29167

AN:

151970

Hom.:

3083

Cov.:

show subpopulations

Gnomad AFR

AF:

0.258

Gnomad AMI

AF:

0.160

Gnomad AMR

AF:

0.135

Gnomad ASJ

AF:

0.146

Gnomad EAS

AF:

0.0201

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.170

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.186

Gnomad OTH

AF:

0.188

GnomAD4 exome

AF:

0.177

AC:

251173

AN:

1419528

Hom.:

23264

AF XY:

0.176

AC XY:

124654

AN XY:

707288

show subpopulations

African (AFR)

AF:

0.264

AC:

8622

AN:

32640

American (AMR)

AF:

0.0932

AC:

4023

AN:

43160

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

3682

AN:

25622

East Asian (EAS)

AF:

0.0167

AC:

651

AN:

39058

South Asian (SAS)

AF:

0.157

AC:

13216

AN:

84408

European-Finnish (FIN)

AF:

0.175

AC:

9099

AN:

52058

Middle Eastern (MID)

AF:

0.189

AC:

807

AN:

4276

European-Non Finnish (NFE)

AF:

0.186

AC:

200556

AN:

1079506

Other (OTH)

AF:

0.179

AC:

10517

AN:

58800

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

10398

20797

31195

41594

51992

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6918

13836

20754

27672

34590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.192

AC:

29215

AN:

152088

Hom.:

3094

Cov.:

AF XY:

0.189

AC XY:

14081

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.258

AC:

10700

AN:

41472

American (AMR)

AF:

0.135

AC:

2068

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.146

AC:

505

AN:

3468

East Asian (EAS)

AF:

0.0201

AC:

104

AN:

5170

South Asian (SAS)

AF:

0.161

AC:

776

AN:

4806

European-Finnish (FIN)

AF:

0.170

AC:

1803

AN:

10598

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.186

AC:

12656

AN:

67966

Other (OTH)

AF:

0.187

AC:

395

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1178

2356

3535

4713

5891

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

308

616

924

1232

1540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.179

Hom.:

9469

Bravo

AF:

0.191

Asia WGS

AF:

0.115

AC:

405

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.0

(source)

DANN

Benign

0.73

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over