rs36020

Variant names:

Variant summary

Our verdict is The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_001172501.3(SLC6A2):c.645-5967C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.114 (AC=17,255) in the gnomAD database across 151,980 control chromosomes, including 1,082 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.159. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 1082 hom., cov: 32)

Consequence

SLC6A2
NM_001172501.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.28

Publications

8 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 due to NET deficiency
Inheritance: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

SLC6A2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001172501.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

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

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1586 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001172501.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC6A2	NM_001172501.3	MANE Select	c.645-5967C>T	intron	N/A	NP_001165972.1	P23975-1
SLC6A2	NM_001172504.1		c.645-5967C>T	intron	N/A	NP_001165975.1	P23975-2
SLC6A2	NM_001043.3		c.645-5967C>T	intron	N/A	NP_001034.1	P23975-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC6A2	ENST00000568943.6	TSL:1 MANE Select	c.645-5967C>T	intron	N/A	ENSP00000457473.1	P23975-1
SLC6A2	ENST00000379906.6	TSL:1	c.645-5967C>T	intron	N/A	ENSP00000369237.2	P23975-1
SLC6A2	ENST00000219833.13	TSL:5	c.645-5967C>T	intron	N/A	ENSP00000219833.8	P23975-2

Frequencies

GnomAD3 genomes

AF:

0.114

AC:

17241

AN:

151886

Hom.:

1078

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0590

Gnomad AMI

AF:

0.0570

Gnomad AMR

AF:

0.101

Gnomad ASJ

AF:

0.133

Gnomad EAS

AF:

0.168

Gnomad SAS

AF:

0.0788

Gnomad FIN

AF:

0.168

Gnomad MID

AF:

0.173

Gnomad NFE

AF:

0.139

Gnomad OTH

AF:

0.120

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.114

AC:

17255

AN:

151980

Hom.:

1082

Cov.:

AF XY:

0.114

AC XY:

8432

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.0589

AC:

2444

AN:

41464

American (AMR)

AF:

0.101

AC:

1544

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.133

AC:

462

AN:

3466

East Asian (EAS)

AF:

0.168

AC:

869

AN:

5178

South Asian (SAS)

AF:

0.0794

AC:

381

AN:

4800

European-Finnish (FIN)

AF:

0.168

AC:

1764

AN:

10512

Middle Eastern (MID)

AF:

0.193

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.139

AC:

9422

AN:

67994

Other (OTH)

AF:

0.124

AC:

261

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

790

1580

2370

3160

3950

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

200

400

600

800

1000

<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:

0.126

Hom.:

1871

Bravo

AF:

0.107

Asia WGS

AF:

0.130

AC:

452

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.162

AC:

19847

AN:

122456

Turkish Variome

AF:

0.106

AC:

164

AN:

1546

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.181

AC:

1622

AN:

8960

Hom.:

154

ABraOM SABE-WGS-1171

AF:

0.128

AC:

300

AN:

2342

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.075

(source)

DANN

Benign

0.21

PhyloP100

-3.3

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

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over