rs47958

Variant names:

• chr16-55692550-C-A
• rs47958
• NM_001172501.3:c.918+498C>A

Variant summary

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

The ENST00000568943.6(SLC6A2):​c.918+498C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 152,012 control chromosomes in the GnomAD database, including 13,214 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 0.41 (13214 hom., cov: 32)
• Consequence: SLC6A2 ENST00000568943.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60
• Publications: 10 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000568943.6. 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.918+498C>A		intron	N/A	NP_001165972.1
	SLC6A2	NM_001172504.1		c.918+498C>A		intron	N/A	NP_001165975.1
	SLC6A2	NM_001043.3		c.918+498C>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.918+498C>A		intron	N/A	ENSP00000457473.1
	SLC6A2	ENST00000379906.6	TSL:1	c.918+498C>A		intron	N/A	ENSP00000369237.2
	SLC6A2	ENST00000219833.13	TSL:5	c.918+498C>A		intron	N/A	ENSP00000219833.8

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62266 AN: 151894 Hom.: 13210 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.435

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.518

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.421

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

GnomAD4 genome AF: 0.410 AC: 62291 AN: 152012 Hom.: 13214 Cov.: 32 AF XY: 0.411 AC XY: 30545 AN XY: 74304

African (AFR) AF: 0.287 AC: 11898 AN: 41452

American (AMR) AF: 0.431 AC: 6586 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1879 AN: 3470

East Asian (EAS) AF: 0.519 AC: 2674 AN: 5154

South Asian (SAS) AF: 0.451 AC: 2175 AN: 4822

European-Finnish (FIN) AF: 0.465 AC: 4914 AN: 10568

Middle Eastern (MID) AF: 0.408 AC: 119 AN: 292

European-Non Finnish (NFE) AF: 0.453 AC: 30754 AN: 67956

Other (OTH) AF: 0.424 AC: 895 AN: 2110

Alfa AF: 0.430 Hom.: 3511

Bravo AF: 0.403

Asia WGS AF: 0.463 AC: 1609 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.16
DANN	Benign	0.32
PhyloP100		-1.6
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: rs47958; hg19: chr16-55726462;