rs10521329

Variant names:

• chr16-55686546-C-A
• rs10521329
• NM_001172501.3:c.783+1265C>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.783+1265C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 152,060 control chromosomes in the GnomAD database, including 3,414 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 0.20 (3414 hom., cov: 32)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.466
• Publications: 12 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A2	NM_001172501.3	c.783+1265C>A		intron_variant	Intron 5 of 14	ENST00000568943.6	NP_001165972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A2	ENST00000568943.6	c.783+1265C>A		intron_variant	Intron 5 of 14	1	NM_001172501.3	ENSP00000457473.1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30725 AN: 151942 Hom.: 3407 Cov.: 32

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.0299

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.196

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

GnomAD4 genome AF: 0.202 AC: 30753 AN: 152060 Hom.: 3414 Cov.: 32 AF XY: 0.199 AC XY: 14807 AN XY: 74314

African (AFR) AF: 0.281 AC: 11642 AN: 41442

American (AMR) AF: 0.145 AC: 2221 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 481 AN: 3466

East Asian (EAS) AF: 0.0298 AC: 154 AN: 5174

South Asian (SAS) AF: 0.185 AC: 892 AN: 4822

European-Finnish (FIN) AF: 0.171 AC: 1802 AN: 10566

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12934 AN: 67982

Other (OTH) AF: 0.196 AC: 414 AN: 2114

Alfa AF: 0.189 Hom.: 1048

Bravo AF: 0.201

Asia WGS AF: 0.122 AC: 428 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.4
DANN	Benign	0.72
PhyloP100		0.47
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: rs10521329; hg19: chr16-55720458;