rs1805065

Positions:

chr16-55669586-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC6A2. . Gene score misZ 2.0193 (greater than the threshold 3.09). Trascript score misZ 3.3305 (greater than threshold 3.09). GenCC has associacion of gene with postural orthostatic tachycardia syndrome.

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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1621 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A2	NM_001172501.3 linkuse as main transcript	c.296C>T	p.Thr99Ile	missense_variant	3/15	ENST00000568943.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A2	ENST00000568943.6 linkuse as main transcript	c.296C>T	p.Thr99Ile	missense_variant	3/15	1	NM_001172501.3	P1	P23975-1

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

GnomAD3 exomes

AF:

0.00950

AC:

2388

AN:

251340

Hom.:

AF XY:

0.00953

AC XY:

1295

AN XY:

135840

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 SAS exome

AF:

0.00457

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

Gnomad4 AFR exome

AF:

0.00233

Gnomad4 AMR exome

AF:

0.00586

Gnomad4 ASJ exome

AF:

0.00719

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00448

Gnomad4 FIN exome

AF:

0.00271

Gnomad4 NFE exome

AF:

0.0207

Gnomad4 OTH exome

AF:

0.0178

GnomAD4 genome

AF:

0.0106

AC:

1621

AN:

152300

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

758

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00354

Gnomad4 AMR

AF:

0.0122

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00229

Gnomad4 FIN

AF:

0.00348

Gnomad4 NFE

AF:

0.0173

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.0149

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

SLC6A2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 27, 2019

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

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

Uncertain

0.86

.;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;.

MutationTaster

Benign

0.68

D;D;D;D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.060

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

REVEL

Benign

0.20

Sift

Benign

0.78

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

Sift4G

Benign

0.43

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

Polyphen

0.0010

B;.;.;.;B;.;.;.

Vest4

0.19

MVP

0.70

MPC

0.79

ClinPred

0.0085

GERP RS

4.9

Varity_R

0.084

gMVP

0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over