16-55672162-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001172501.3(SLC6A2):​c.631G>A​(p.Ala211Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,614,208 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 1 hom. )

Consequence

SLC6A2
NM_001172501.3 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.97
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.059962362).
BS2
High AC in GnomAd4 at 68 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC6A2NM_001172501.3 linkc.631G>A p.Ala211Thr missense_variant 4/15 ENST00000568943.6 NP_001165972.1 P23975-1A0A024R6T9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC6A2ENST00000568943.6 linkc.631G>A p.Ala211Thr missense_variant 4/151 NM_001172501.3 ENSP00000457473.1 P23975-1

Frequencies

GnomAD3 genomes
AF:
0.000447
AC:
68
AN:
152202
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00432
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000112
AC:
28
AN:
251086
Hom.:
1
AF XY:
0.000118
AC XY:
16
AN XY:
135684
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000781
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000246
AC:
36
AN:
1461888
Hom.:
1
Cov.:
31
AF XY:
0.0000289
AC XY:
21
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000604
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000446
AC:
68
AN:
152320
Hom.:
0
Cov.:
33
AF XY:
0.000564
AC XY:
42
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00431
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000400
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 28, 2024The c.631G>A (p.A211T) alteration is located in exon 3 (coding exon 3) of the SLC6A2 gene. This alteration results from a G to A substitution at nucleotide position 631, causing the alanine (A) at amino acid position 211 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
23
DANN
Benign
0.95
DEOGEN2
Benign
0.096
T;.;T;T;T;.;T;.
Eigen
Benign
0.013
Eigen_PC
Benign
0.20
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
.;D;D;D;D;D;D;D
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.060
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
0.51
N;.;.;N;.;N;.;.
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-1.6
N;N;N;N;N;N;N;N
REVEL
Benign
0.18
Sift
Benign
0.34
T;T;T;T;T;T;T;T
Sift4G
Benign
0.54
T;T;T;T;T;T;T;T
Polyphen
0.30
B;.;.;B;.;.;.;.
Vest4
0.55
MVP
0.75
MPC
0.89
ClinPred
0.14
T
GERP RS
4.8
Varity_R
0.22
gMVP
0.57

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.

Other links and lift over

dbSNP: rs188235131; hg19: chr16-55706074; API