rs192303

Variant names:

• chr16-55666312-C-G
• rs192303
• NM_001172501.3:c.275-3253C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001172501.3(SLC6A2):​c.275-3253C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 152,106 control chromosomes in the GnomAD database, including 6,771 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (6771 hom., cov: 32)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0870
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 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.275-3253C>G		intron	N/A	NP_001165972.1	P23975-1
	SLC6A2	NM_001172504.1		c.275-3253C>G		intron	N/A	NP_001165975.1	P23975-2
	SLC6A2	NM_001043.3		c.275-3253C>G		intron	N/A	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.275-3253C>G		intron	N/A	ENSP00000457473.1	P23975-1
	SLC6A2	ENST00000379906.6	TSL:1	c.275-3253C>G		intron	N/A	ENSP00000369237.2	P23975-1
	SLC6A2	ENST00000219833.13	TSL:5	c.275-3253C>G		intron	N/A	ENSP00000219833.8	P23975-2

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44674 AN: 151986 Hom.: 6763 Cov.: 32

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.275

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.294 AC: 44712 AN: 152106 Hom.: 6771 Cov.: 32 AF XY: 0.291 AC XY: 21664 AN XY: 74366

African (AFR) AF: 0.319 AC: 13213 AN: 41466

American (AMR) AF: 0.249 AC: 3805 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1044 AN: 3466

East Asian (EAS) AF: 0.141 AC: 732 AN: 5176

South Asian (SAS) AF: 0.190 AC: 916 AN: 4822

European-Finnish (FIN) AF: 0.320 AC: 3394 AN: 10594

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20821 AN: 67982

Other (OTH) AF: 0.276 AC: 582 AN: 2112

Alfa AF: 0.299 Hom.: 969

Bravo AF: 0.290

Asia WGS AF: 0.190 AC: 661 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.4
DANN	Benign	0.74
PhyloP100		-0.087
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs192303; hg19: chr16-55700224;