rs1805066

Positions:

chr16-55685231-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_001172501.3(SLC6A2):c.733G>A(p.Val245Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00879 in 1,614,014 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.0060 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0091 ( 73 hom. )

Consequence

SLC6A2
NM_001172501.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.26

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 -15 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=0.0048825443).

BP6

Variant 16-55685231-G-A is Benign according to our data. Variant chr16-55685231-G-A is described in ClinVar as [Benign]. Clinvar id is 769421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 920 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A2	NM_001172501.3 linkuse as main transcript	c.733G>A	p.Val245Ile	missense_variant	5/15	ENST00000568943.6	NP_001165972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A2	ENST00000568943.6 linkuse as main transcript	c.733G>A	p.Val245Ile	missense_variant	5/15	1	NM_001172501.3	ENSP00000457473	P1	P23975-1

Frequencies

GnomAD3 genomes

AF:

0.00605

AC:

921

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00819

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00607

AC:

1525

AN:

251440

Hom.:

AF XY:

0.00603

AC XY:

819

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.000652

Gnomad SAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.00905

Gnomad NFE exome

AF:

0.0100

Gnomad OTH exome

AF:

0.00799

GnomAD4 exome

AF:

0.00908

AC:

13273

AN:

1461700

Hom.:

Cov.:

AF XY:

0.00880

AC XY:

6400

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.00177

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00161

Gnomad4 FIN exome

AF:

0.0107

Gnomad4 NFE exome

AF:

0.0108

Gnomad4 OTH exome

AF:

0.00757

GnomAD4 genome

AF:

0.00604

AC:

920

AN:

152314

Hom.:

Cov.:

AF XY:

0.00564

AC XY:

420

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00171

Gnomad4 AMR

AF:

0.00274

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00819

Gnomad4 NFE

AF:

0.0104

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00840

Hom.:

Bravo

AF:

0.00534

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00907

AC:

ExAC

AF:

0.00609

AC:

739

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	SLC6A2: BP4, BS1, BS2 -

SLC6A2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 2019

This variant is classified as likely 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

0.080

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.090

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

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.75

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

M_CAP

Benign

0.016

MetaRNN

Benign

0.0049

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.72

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.32

PROVEAN

Benign

0.47

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

REVEL

Benign

0.14

Sift

Benign

0.42

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

Sift4G

Benign

0.47

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

Polyphen

0.0

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

Vest4

0.21

MVP

0.64

MPC

0.59

ClinPred

0.0021

GERP RS

3.3

Varity_R

0.037

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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