16-55684906-G-C

Variant names:

• chr16-55684906-G-C
• rs36017
• NM_001172501.3:c.645-237G>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.645-237G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 152,090 control chromosomes in the GnomAD database, including 14,014 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 0.43 (14014 hom., cov: 33)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.501
• Publications: 18 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: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

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 (EAS) allele frequency at 95% confidence interval = 0.503 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	NM_001172501.3	MANE Select	c.645-237G>C		intron	N/A	NP_001165972.1	P23975-1
	SLC6A2	NM_001172504.1		c.645-237G>C		intron	N/A	NP_001165975.1	P23975-2
	SLC6A2	NM_001043.3		c.645-237G>C		intron	N/A	NP_001034.1	P23975-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	ENST00000568943.6	TSL:1 MANE Select	c.645-237G>C		intron	N/A	ENSP00000457473.1	P23975-1
	SLC6A2	ENST00000379906.6	TSL:1	c.645-237G>C		intron	N/A	ENSP00000369237.2	P23975-1
	SLC6A2	ENST00000219833.13	TSL:5	c.645-237G>C		intron	N/A	ENSP00000219833.8	P23975-2

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64640 AN: 151972 Hom.: 14007 Cov.: 33

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.437

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

GnomAD4 genome AF: 0.425 AC: 64677 AN: 152090 Hom.: 14014 Cov.: 33 AF XY: 0.426 AC XY: 31659 AN XY: 74342

African (AFR) AF: 0.333 AC: 13824 AN: 41480

American (AMR) AF: 0.439 AC: 6706 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1948 AN: 3470

East Asian (EAS) AF: 0.520 AC: 2685 AN: 5168

South Asian (SAS) AF: 0.454 AC: 2189 AN: 4822

European-Finnish (FIN) AF: 0.466 AC: 4923 AN: 10572

Middle Eastern (MID) AF: 0.425 AC: 124 AN: 292

European-Non Finnish (NFE) AF: 0.455 AC: 30951 AN: 67980

Other (OTH) AF: 0.440 AC: 930 AN: 2114

Alfa AF: 0.317 Hom.: 944

Bravo AF: 0.421

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.27
DANN	Benign	0.42
PhyloP100		-0.50
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: rs36017; hg19: chr16-55718818;