NM_001172501.3:c.645-2215G>A

Variant names:

• chr16-55682928-G-A
• rs40147
• NM_001172501.3:c.645-2215G>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.645-2215G>A 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 152,090 control chromosomes in the GnomAD database, including 6,821 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 (6821 hom., cov: 32)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.134
• 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=-1.01).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.39 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.645-2215G>A		intron	N/A	NP_001165972.1
	SLC6A2	NM_001172504.1		c.645-2215G>A		intron	N/A	NP_001165975.1
	SLC6A2	NM_001043.3		c.645-2215G>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.645-2215G>A		intron	N/A	ENSP00000457473.1
	SLC6A2	ENST00000379906.6	TSL:1	c.645-2215G>A		intron	N/A	ENSP00000369237.2
	SLC6A2	ENST00000219833.13	TSL:5	c.645-2215G>A		intron	N/A	ENSP00000219833.8

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44696 AN: 151970 Hom.: 6807 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.291

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

GnomAD4 genome AF: 0.294 AC: 44744 AN: 152090 Hom.: 6821 Cov.: 32 AF XY: 0.297 AC XY: 22108 AN XY: 74336

African (AFR) AF: 0.215 AC: 8921 AN: 41490

American (AMR) AF: 0.369 AC: 5648 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1206 AN: 3468

East Asian (EAS) AF: 0.293 AC: 1505 AN: 5140

South Asian (SAS) AF: 0.405 AC: 1955 AN: 4824

European-Finnish (FIN) AF: 0.329 AC: 3476 AN: 10576

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.309 AC: 21007 AN: 67986

Other (OTH) AF: 0.292 AC: 617 AN: 2112

Alfa AF: 0.302 Hom.: 13394

Bravo AF: 0.293

Asia WGS AF: 0.314 AC: 1093 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.2
DANN	Benign	0.63
PhyloP100		0.13
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: rs40147; hg19: chr16-55716840;