16-55697923-G-A

Variant names:

• chr16-55697923-G-A
• rs5569
• NM_001172501.3:c.1287G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001172501.3(SLC6A2):​c.1287G>A​(p.Thr429Thr) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.10
• Publications: 149 publications found

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 Gene-Disease associations (from GenCC):

• postural orthostatic tachycardia syndrome

  Inheritance: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 16-55697923-G-A is Benign according to our data. Variant chr16-55697923-G-A is described in ClinVar as Benign. ClinVar VariationId is 1283289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172501.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	NM_001172501.3	MANE Select	c.1287G>A	p.Thr429Thr	synonymous	Exon 10 of 15	NP_001165972.1	P23975-1
	SLC6A2	NM_001172504.1		c.1287G>A	p.Thr429Thr	synonymous	Exon 9 of 14	NP_001165975.1	P23975-2
	SLC6A2	NM_001043.3		c.1287G>A	p.Thr429Thr	synonymous	Exon 9 of 14	NP_001034.1	P23975-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	ENST00000568943.6	TSL:1 MANE Select	c.1287G>A	p.Thr429Thr	synonymous	Exon 10 of 15	ENSP00000457473.1	P23975-1
	SLC6A2	ENST00000379906.6	TSL:1	c.1287G>A	p.Thr429Thr	synonymous	Exon 9 of 14	ENSP00000369237.2	P23975-1
	SLC6A2	ENST00000219833.13	TSL:5	c.1287G>A	p.Thr429Thr	synonymous	Exon 9 of 14	ENSP00000219833.8	P23975-2

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40573 AN: 151886 Hom.: 6249 Cov.: 31

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

GnomAD2 exomes AF: 0.313 AC: 78531 AN: 251250 AF XY: 0.308

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 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

African (AFR) AF: 0.0999 AC: 3345 AN: 33480

American (AMR) AF: 0.399 AC: 17846 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 7125 AN: 26136

East Asian (EAS) AF: 0.273 AC: 10841 AN: 39694

South Asian (SAS) AF: 0.202 AC: 17385 AN: 86252

European-Finnish (FIN) AF: 0.344 AC: 18366 AN: 53414

Middle Eastern (MID) AF: 0.240 AC: 1383 AN: 5754

European-Non Finnish (NFE) AF: 0.347 AC: 386189 AN: 1111678

Other (OTH) AF: 0.301 AC: 18167 AN: 60386

GnomAD4 genome AF: 0.267 AC: 40580 AN: 152004 Hom.: 6254 Cov.: 31 AF XY: 0.269 AC XY: 19969 AN XY: 74300

African (AFR) AF: 0.114 AC: 4726 AN: 41466

American (AMR) AF: 0.332 AC: 5068 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 917 AN: 3470

East Asian (EAS) AF: 0.286 AC: 1472 AN: 5148

South Asian (SAS) AF: 0.191 AC: 920 AN: 4808

European-Finnish (FIN) AF: 0.354 AC: 3733 AN: 10560

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.335 AC: 22744 AN: 67950

Other (OTH) AF: 0.256 AC: 542 AN: 2114

Alfa AF: 0.312 Hom.: 25675

Bravo AF: 0.261

Asia WGS AF: 0.208 AC: 722 AN: 3478

EpiCase AF: 0.319

EpiControl AF: 0.330

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.54
DANN	Benign	0.75
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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