16-55684972-T-C

Variant names:

• chr16-55684972-T-C
• rs2270935
• NM_001172501.3:c.645-171T>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.645-171T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.937 in 152,328 control chromosomes in the GnomAD database, including 67,026 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 0.94 (67026 hom., cov: 34)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.55
• Publications: 6 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.971 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.645-171T>C		intron	N/A	NP_001165972.1	P23975-1
	SLC6A2	NM_001172504.1		c.645-171T>C		intron	N/A	NP_001165975.1	P23975-2
	SLC6A2	NM_001043.3		c.645-171T>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.645-171T>C		intron	N/A	ENSP00000457473.1	P23975-1
	SLC6A2	ENST00000379906.6	TSL:1	c.645-171T>C		intron	N/A	ENSP00000369237.2	P23975-1
	SLC6A2	ENST00000219833.13	TSL:5	c.645-171T>C		intron	N/A	ENSP00000219833.8	P23975-2

Frequencies

GnomAD3 genomes AF: 0.937 AC: 142555 AN: 152210 Hom.: 66981 Cov.: 34

Gnomad AFR AF: 0.873

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.933

Gnomad ASJ AF: 0.966

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.915

Gnomad FIN AF: 0.990

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.977

Gnomad OTH AF: 0.929

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

GnomAD4 genome AF: 0.937 AC: 142659 AN: 152328 Hom.: 67026 Cov.: 34 AF XY: 0.936 AC XY: 69745 AN XY: 74482

African (AFR) AF: 0.873 AC: 36273 AN: 41562

American (AMR) AF: 0.933 AC: 14290 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.966 AC: 3355 AN: 3472

East Asian (EAS) AF: 0.803 AC: 4147 AN: 5164

South Asian (SAS) AF: 0.915 AC: 4421 AN: 4830

European-Finnish (FIN) AF: 0.990 AC: 10520 AN: 10624

Middle Eastern (MID) AF: 0.966 AC: 284 AN: 294

European-Non Finnish (NFE) AF: 0.977 AC: 66493 AN: 68044

Other (OTH) AF: 0.928 AC: 1964 AN: 2116

Alfa AF: 0.969 Hom.: 3364

Bravo AF: 0.927

Asia WGS AF: 0.863 AC: 3002 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.20
DANN	Benign	0.74
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: rs2270935; hg19: chr16-55718884;