rs8049681

Variant names:

• chr16-55701438-G-A
• rs8049681
• NM_001172501.3:c.1759-425G>A

Variant summary

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

The NM_001172501.3(SLC6A2):​c.1759-425G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 152,060 control chromosomes in the GnomAD database, including 3,770 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 0.21 (3770 hom., cov: 32)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.580
• Publications: 2 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: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A2	NM_001172501.3	c.1759-425G>A		intron_variant	Intron 13 of 14	ENST00000568943.6	NP_001165972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A2	ENST00000568943.6	c.1759-425G>A		intron_variant	Intron 13 of 14	1	NM_001172501.3	ENSP00000457473.1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31295 AN: 151940 Hom.: 3758 Cov.: 32

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.0336

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.202

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

GnomAD4 genome AF: 0.206 AC: 31353 AN: 152060 Hom.: 3770 Cov.: 32 AF XY: 0.205 AC XY: 15263 AN XY: 74318

African (AFR) AF: 0.336 AC: 13904 AN: 41442

American (AMR) AF: 0.130 AC: 1985 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 544 AN: 3472

East Asian (EAS) AF: 0.0337 AC: 174 AN: 5170

South Asian (SAS) AF: 0.202 AC: 972 AN: 4822

European-Finnish (FIN) AF: 0.192 AC: 2035 AN: 10576

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11046 AN: 67980

Other (OTH) AF: 0.201 AC: 422 AN: 2104

Alfa AF: 0.175 Hom.: 918

Bravo AF: 0.207

Asia WGS AF: 0.133 AC: 466 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.0
DANN	Benign	0.29
PhyloP100		0.58
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: rs8049681; hg19: chr16-55735350;