16-55699677-T-C

Variant names:

• chr16-55699677-T-C
• rs1800887
• NM_001172501.3:c.1590+23T>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.1590+23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 1,519,906 control chromosomes in the GnomAD database, including 47,456 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 0.30 (8104 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39352 hom.)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.43
• 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A2	NM_001172501.3	c.1590+23T>C		intron_variant	Intron 12 of 14	ENST00000568943.6	NP_001165972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A2	ENST00000568943.6	c.1590+23T>C		intron_variant	Intron 12 of 14	1	NM_001172501.3	ENSP00000457473.1

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45126 AN: 151942 Hom.: 8080 Cov.: 32

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.0422

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.272

GnomAD2 exomes AF: 0.228 AC: 56758 AN: 249332 AF XY: 0.232

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.0411

Gnomad FIN exome AF: 0.288

Gnomad NFE exome AF: 0.221

Gnomad OTH exome AF: 0.222

GnomAD4 exome AF: 0.231 AC: 316361 AN: 1367846 Hom.: 39352 Cov.: 22 AF XY: 0.234 AC XY: 160300 AN XY: 685760

African (AFR) AF: 0.516 AC: 16551 AN: 32072

American (AMR) AF: 0.122 AC: 5443 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 5523 AN: 25560

East Asian (EAS) AF: 0.0335 AC: 1314 AN: 39190

South Asian (SAS) AF: 0.310 AC: 26173 AN: 84378

European-Finnish (FIN) AF: 0.279 AC: 14866 AN: 53284

Middle Eastern (MID) AF: 0.263 AC: 1477 AN: 5620

European-Non Finnish (NFE) AF: 0.225 AC: 231091 AN: 1025900

Other (OTH) AF: 0.243 AC: 13923 AN: 57336

GnomAD4 genome AF: 0.297 AC: 45203 AN: 152060 Hom.: 8104 Cov.: 32 AF XY: 0.299 AC XY: 22213 AN XY: 74316

African (AFR) AF: 0.500 AC: 20716 AN: 41450

American (AMR) AF: 0.184 AC: 2814 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 766 AN: 3470

East Asian (EAS) AF: 0.0423 AC: 218 AN: 5156

South Asian (SAS) AF: 0.317 AC: 1525 AN: 4818

European-Finnish (FIN) AF: 0.292 AC: 3095 AN: 10592

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15153 AN: 67972

Other (OTH) AF: 0.271 AC: 573 AN: 2114

Alfa AF: 0.245 Hom.: 13951

Bravo AF: 0.294

Asia WGS AF: 0.217 AC: 757 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.094
DANN	Benign	0.43
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800887; hg19: chr16-55733589; COSMIC: COSV54915974; COSMIC: COSV54915974;