Genetic Variant SLC6A2:c.1261-141C>A (chr16-55697756-C-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.1261-141C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0503 in 781,954 control chromosomes in the GnomAD database, including 2,489 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 0.075 ( 845 hom., cov: 32)

Exomes 𝑓: 0.044 ( 1644 hom. )

Consequence

SLC6A2
NM_001172501.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.43

Publications

3 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=-0.79).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A2	NM_001172501.3 link	c.1261-141C>A		intron_variant	Intron 9 of 14	ENST00000568943.6	NP_001165972.1	P23975-1A0A024R6T9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A2	ENST00000568943.6 link	c.1261-141C>A		intron_variant	Intron 9 of 14	1	NM_001172501.3	ENSP00000457473.1		P23975-1

Frequencies

GnomAD3 genomes

AF:

0.0747

AC:

11352

AN:

152022

Hom.:

846

Cov.:

show subpopulations

Gnomad AFR

AF:

0.162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0687

Gnomad ASJ

AF:

0.0303

Gnomad EAS

AF:

0.256

Gnomad SAS

AF:

0.0824

Gnomad FIN

AF:

0.0157

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0211

Gnomad OTH

AF:

0.0741

GnomAD4 exome

AF:

0.0444

AC:

27966

AN:

629812

Hom.:

1644

AF XY:

0.0449

AC XY:

14839

AN XY:

330636

show subpopulations

African (AFR)

AF:

0.165

AC:

2774

AN:

16774

American (AMR)

AF:

0.0690

AC:

1973

AN:

28580

Ashkenazi Jewish (ASJ)

AF:

0.0302

AC:

530

AN:

17570

East Asian (EAS)

AF:

0.247

AC:

7901

AN:

31960

South Asian (SAS)

AF:

0.0790

AC:

4554

AN:

57652

European-Finnish (FIN)

AF:

0.0190

AC:

706

AN:

37148

Middle Eastern (MID)

AF:

0.0530

AC:

129

AN:

2436

European-Non Finnish (NFE)

AF:

0.0193

AC:

7817

AN:

405286

Other (OTH)

AF:

0.0488

AC:

1582

AN:

32406

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

1297

2593

3890

5186

6483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

260

520

780

1040

1300

<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:

0.0747

AC:

11362

AN:

152142

Hom.:

845

Cov.:

AF XY:

0.0757

AC XY:

5633

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.163

AC:

6742

AN:

41486

American (AMR)

AF:

0.0684

AC:

1047

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0303

AC:

105

AN:

3470

East Asian (EAS)

AF:

0.255

AC:

1308

AN:

5128

South Asian (SAS)

AF:

0.0822

AC:

396

AN:

4816

European-Finnish (FIN)

AF:

0.0157

AC:

167

AN:

10606

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0211

AC:

1432

AN:

68020

Other (OTH)

AF:

0.0738

AC:

156

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

503

1006

1510

2013

2516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

252

378

504

630

<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:

0.0483

Hom.:

Bravo

AF:

0.0841

Asia WGS

AF:

0.158

AC:

548

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.81

(source)

DANN

Benign

0.86

PhyloP100

-1.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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