16-55669136-T-C

Variant names:

• chr16-55669136-T-C
• rs13333066
• NM_001172501.3:c.275-429T>C

Variant summary

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

The NM_001172501.3(SLC6A2):​c.275-429T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 151,990 control chromosomes in the GnomAD database, including 36,450 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 0.69 (36450 hom., cov: 31)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.621
• Publications: 9 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.716 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.275-429T>C		intron	N/A	NP_001165972.1
	SLC6A2	NM_001172504.1		c.275-429T>C		intron	N/A	NP_001165975.1
	SLC6A2	NM_001043.3		c.275-429T>C		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.275-429T>C		intron	N/A	ENSP00000457473.1
	SLC6A2	ENST00000379906.6	TSL:1	c.275-429T>C		intron	N/A	ENSP00000369237.2
	SLC6A2	ENST00000219833.13	TSL:5	c.275-429T>C		intron	N/A	ENSP00000219833.8

Frequencies

GnomAD3 genomes AF: 0.691 AC: 104948 AN: 151872 Hom.: 36434 Cov.: 31

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.719

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.689

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

GnomAD4 genome AF: 0.691 AC: 105013 AN: 151990 Hom.: 36450 Cov.: 31 AF XY: 0.694 AC XY: 51538 AN XY: 74290

African (AFR) AF: 0.632 AC: 26186 AN: 41444

American (AMR) AF: 0.700 AC: 10701 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 2495 AN: 3468

East Asian (EAS) AF: 0.612 AC: 3153 AN: 5156

South Asian (SAS) AF: 0.701 AC: 3374 AN: 4814

European-Finnish (FIN) AF: 0.739 AC: 7795 AN: 10550

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.721 AC: 49021 AN: 67964

Other (OTH) AF: 0.693 AC: 1459 AN: 2106

Alfa AF: 0.706 Hom.: 15403

Bravo AF: 0.685

Asia WGS AF: 0.632 AC: 2195 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.5
DANN	Benign	0.47
PhyloP100		-0.62
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: rs13333066; hg19: chr16-55703048;