16-55672162-G-A
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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
NM_001172501.3 missense
Scores
1
2
16
Clinical Significance
Conservation
PhyloP100: 7.97
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]
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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 |
---|---|---|---|---|---|---|---|---|
SLC6A2 | NM_001172501.3 | c.631G>A | p.Ala211Thr | missense_variant | 4/15 | ENST00000568943.6 | NP_001165972.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000447 AC: 68AN: 152202Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000112 AC: 28AN: 251086Hom.: 1 AF XY: 0.000118 AC XY: 16AN XY: 135684
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GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461888Hom.: 1 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 727244
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GnomAD4 genome AF: 0.000446 AC: 68AN: 152320Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42AN XY: 74488
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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 submitter | clinical testing | Ambry Genetics | Mar 28, 2024 | The 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;T;T;T;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.;N;.;N;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N;N;N
REVEL
Benign
Sift
Benign
T;T;T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T
Polyphen
B;.;.;B;.;.;.;.
Vest4
MVP
MPC
0.89
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at