16-55660371-T-C

Variant names:

• chr16-55660371-T-C
• rs17307096
• NM_001172501.3:c.274+3403T>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.274+3403T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 152,070 control chromosomes in the GnomAD database, including 31,370 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 0.64 (31370 hom., cov: 33)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.28
• Publications: 3 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.664 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.274+3403T>C		intron	N/A	NP_001165972.1
	SLC6A2	NM_001172504.1		c.274+3403T>C		intron	N/A	NP_001165975.1
	SLC6A2	NM_001043.3		c.274+3403T>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.274+3403T>C		intron	N/A	ENSP00000457473.1
	SLC6A2	ENST00000379906.6	TSL:1	c.274+3403T>C		intron	N/A	ENSP00000369237.2
	SLC6A2	ENST00000219833.13	TSL:5	c.274+3403T>C		intron	N/A	ENSP00000219833.8

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97241 AN: 151952 Hom.: 31340 Cov.: 33

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.665

Gnomad ASJ AF: 0.644

Gnomad EAS AF: 0.609

Gnomad SAS AF: 0.634

Gnomad FIN AF: 0.722

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.669

Gnomad OTH AF: 0.643

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

GnomAD4 genome AF: 0.640 AC: 97326 AN: 152070 Hom.: 31370 Cov.: 33 AF XY: 0.645 AC XY: 47899 AN XY: 74314

African (AFR) AF: 0.566 AC: 23493 AN: 41480

American (AMR) AF: 0.664 AC: 10152 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 2236 AN: 3470

East Asian (EAS) AF: 0.608 AC: 3137 AN: 5156

South Asian (SAS) AF: 0.635 AC: 3061 AN: 4820

European-Finnish (FIN) AF: 0.722 AC: 7633 AN: 10578

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.669 AC: 45503 AN: 67980

Other (OTH) AF: 0.648 AC: 1362 AN: 2102

Alfa AF: 0.659 Hom.: 115879

Bravo AF: 0.632

Asia WGS AF: 0.609 AC: 2117 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.47
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17307096; hg19: chr16-55694283;