rs1805065

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001172501.3(SLC6A2):c.296C>T(p.Thr99Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,613,980 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 13 hom., cov: 32)

Exomes 𝑓: 0.017 ( 274 hom. )

Consequence

SLC6A2
NM_001172501.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.25

Publications

24 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070825815).

BP6

Variant 16-55669586-C-T is Benign according to our data. Variant chr16-55669586-C-T is described in ClinVar as Benign. ClinVar VariationId is 778123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0106 (1621/152300) while in subpopulation NFE AF = 0.0173 (1176/68024). AF 95% confidence interval is 0.0165. There are 13 homozygotes in GnomAd4. There are 758 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1621 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A2	NM_001172501.3 link	c.296C>T	p.Thr99Ile	missense_variant	Exon 3 of 15	ENST00000568943.6	NP_001165972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A2	ENST00000568943.6 link	c.296C>T	p.Thr99Ile	missense_variant	Exon 3 of 15	1	NM_001172501.3	ENSP00000457473.1

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1621

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00355

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00348

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0173

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00950

AC:

2388

AN:

251340

AF XY:

0.00953

show subpopulations

Gnomad AFR exome

AF:

0.00283

Gnomad AMR exome

AF:

0.00558

Gnomad ASJ exome

AF:

0.00804

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00231

Gnomad NFE exome

AF:

0.0159

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.0172

AC:

25156

AN:

1461680

Hom.:

274

Cov.:

AF XY:

0.0167

AC XY:

12170

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

33480

American (AMR)

AF:

0.00586

AC:

262

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00719

AC:

188

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00448

AC:

386

AN:

86250

European-Finnish (FIN)

AF:

0.00271

AC:

145

AN:

53412

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0207

AC:

23018

AN:

1111840

Other (OTH)

AF:

0.0178

AC:

1073

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1208

2416

3625

4833

6041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

898

1796

2694

3592

4490

<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:

0.0106

AC:

1621

AN:

152300

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

758

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00354

AC:

147

AN:

41578

American (AMR)

AF:

0.0122

AC:

187

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00229

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00348

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0173

AC:

1176

AN:

68024

Other (OTH)

AF:

0.0118

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

160

241

321

401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0140

Hom.:

Bravo

AF:

0.0113

TwinsUK

AF:

0.0170

AC:

ALSPAC

AF:

0.0197

AC:

ESP6500AA

AF:

0.00478

AC:

ESP6500EA

AF:

0.0184

AC:

158

ExAC

AF:

0.00937

AC:

1137

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0189

EpiControl

AF:

0.0145

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

SLC6A2-related disorder

Benign:1

Nov 27, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.051

T;.;T;.;T;T;.;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.0

.;D;D;D;D;D;D;D

MetaRNN

Benign

0.0071

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.53

N;.;.;.;N;.;N;.

PhyloP100

1.2

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.060

N;N;N;N;N;N;N;N

REVEL

Benign

0.0

Sift

Benign

0.78

T;T;T;T;T;T;T;T

Sift4G

Benign

0.43

T;T;T;T;T;T;T;T

Vest4

0.19

ClinPred

0.0085

GERP RS

4.9

Varity_R

0.084

gMVP

0.29

Mutation Taster

=99/1

polymorphism

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over