chr16-55694494-G-A

Variant names:

• chr16-55694494-G-A
• rs1861647
• NM_001172501.3:c.1022+381G>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.1022+381G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 152,092 control chromosomes in the GnomAD database, including 7,396 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 (7396 hom., cov: 32)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0150
• Publications: 8 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.368 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	NM_001172501.3	MANE Select	c.1022+381G>A		intron	N/A	NP_001165972.1
	SLC6A2	NM_001172504.1		c.1022+381G>A		intron	N/A	NP_001165975.1
	SLC6A2	NM_001043.3		c.1022+381G>A		intron	N/A	NP_001034.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	ENST00000568943.6	TSL:1 MANE Select	c.1022+381G>A		intron	N/A	ENSP00000457473.1
	SLC6A2	ENST00000379906.6	TSL:1	c.1022+381G>A		intron	N/A	ENSP00000369237.2
	SLC6A2	ENST00000219833.13	TSL:5	c.1022+381G>A		intron	N/A	ENSP00000219833.8

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43963 AN: 151974 Hom.: 7390 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.290

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

GnomAD4 genome AF: 0.289 AC: 43972 AN: 152092 Hom.: 7396 Cov.: 32 AF XY: 0.290 AC XY: 21540 AN XY: 74330

African (AFR) AF: 0.117 AC: 4855 AN: 41522

American (AMR) AF: 0.358 AC: 5472 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1089 AN: 3466

East Asian (EAS) AF: 0.247 AC: 1277 AN: 5162

South Asian (SAS) AF: 0.205 AC: 987 AN: 4826

European-Finnish (FIN) AF: 0.368 AC: 3895 AN: 10570

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.372 AC: 25267 AN: 67942

Other (OTH) AF: 0.287 AC: 606 AN: 2114

Alfa AF: 0.264 Hom.: 1747

Bravo AF: 0.282

Asia WGS AF: 0.202 AC: 704 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.44
PhyloP100		-0.015
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: rs1861647; hg19: chr16-55728406;