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rs5569

chr16-55697923-G-Achr16-55697923-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_001172501.3(SLC6A2):c.1287G>A(p.Thr429=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,613,516 control chromosomes in the GnomAD database, including 88,215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.27 ( 6254 hom., cov: 31)
Exomes 𝑓: 0.33 ( 81961 hom. )

Consequence

SLC6A2
NM_001172501.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.10
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.7).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 16-55697923-G-A is Benign according to our data. Variant chr16-55697923-G-A is described in ClinVar as [Benign]. Clinvar id is 1283289.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-3.1 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC6A2NM_001172501.3 linkuse as main transcriptc.1287G>A p.Thr429= synonymous_variant 10/15 ENST00000568943.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC6A2ENST00000568943.6 linkuse as main transcriptc.1287G>A p.Thr429= synonymous_variant 10/151 NM_001172501.3 P1P23975-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.267
AC:
40573
AN:
151886
Hom.:
6249
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.114
Gnomad AMI
AF:
0.407
Gnomad AMR
AF:
0.331
Gnomad ASJ
AF:
0.264
Gnomad EAS
AF:
0.286
Gnomad SAS
AF:
0.191
Gnomad FIN
AF:
0.354
Gnomad MID
AF:
0.297
Gnomad NFE
AF:
0.335
Gnomad OTH
AF:
0.259
GnomAD3 exomes
AF:
0.313
AC:
78531
AN:
251250
Hom.:
13223
AF XY:
0.308
AC XY:
41781
AN XY:
135800
show subpopulations
Gnomad AFR exome
AF:
0.111
Gnomad AMR exome
AF:
0.411
Gnomad ASJ exome
AF:
0.269
Gnomad EAS exome
AF:
0.306
Gnomad SAS exome
AF:
0.198
Gnomad FIN exome
AF:
0.347
Gnomad NFE exome
AF:
0.341
Gnomad OTH exome
AF:
0.291
GnomAD4 exome
AF:
0.329
AC:
480647
AN:
1461512
Hom.:
81961
Cov.:
40
AF XY:
0.325
AC XY:
236147
AN XY:
727072
show subpopulations
Gnomad4 AFR exome
AF:
0.0999
Gnomad4 AMR exome
AF:
0.399
Gnomad4 ASJ exome
AF:
0.273
Gnomad4 EAS exome
AF:
0.273
Gnomad4 SAS exome
AF:
0.202
Gnomad4 FIN exome
AF:
0.344
Gnomad4 NFE exome
AF:
0.347
Gnomad4 OTH exome
AF:
0.301
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.267
AC:
40580
AN:
152004
Hom.:
6254
Cov.:
31
AF XY:
0.269
AC XY:
19969
AN XY:
74300
show subpopulations
Gnomad4 AFR
AF:
0.114
Gnomad4 AMR
AF:
0.332
Gnomad4 ASJ
AF:
0.264
Gnomad4 EAS
AF:
0.286
Gnomad4 SAS
AF:
0.191
Gnomad4 FIN
AF:
0.354
Gnomad4 NFE
AF:
0.335
Gnomad4 OTH
AF:
0.256
Alfa
AF:
0.317
Hom.:
12973
Bravo
AF:
0.261
Asia WGS
AF:
0.208
AC:
722
AN:
3478
EpiCase
AF:
0.319
EpiControl
AF:
0.330

ClinVar

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

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxSep 28, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.70
Cadd
Benign
0.54
Dann
Benign
0.75

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

LitVar

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

Other links and lift over

dbSNP: rs5569; hg19: chr16-55731835; COSMIC: COSV54916201; COSMIC: COSV54916201; API