rs5564

Variant names:

• chr16-55692063-A-G
• rs5564
• NM_001172501.3:c.918+11A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-55692063-A-G
• chr16-55692063-A-T

Variant summary

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

The NM_001172501.3(SLC6A2):​c.918+11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0726 in 1,613,968 control chromosomes in the GnomAD database, including 4,737 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 0.063 (373 hom., cov: 32)
  • Exomes 𝑓: 0.074 (4364 hom.)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• Publications: 15 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A2	NM_001172501.3	c.918+11A>G		intron_variant	Intron 6 of 14	ENST00000568943.6	NP_001165972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A2	ENST00000568943.6	c.918+11A>G		intron_variant	Intron 6 of 14	1	NM_001172501.3	ENSP00000457473.1

Frequencies

GnomAD3 genomes AF: 0.0635 AC: 9658 AN: 152156 Hom.: 374 Cov.: 32

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.0558

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.0999

Gnomad FIN AF: 0.0864

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0714

Gnomad OTH AF: 0.0736

GnomAD2 exomes AF: 0.0783 AC: 19658 AN: 251150 AF XY: 0.0807

Gnomad AFR exome AF: 0.0244

Gnomad AMR exome AF: 0.0578

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.159

Gnomad FIN exome AF: 0.0886

Gnomad NFE exome AF: 0.0694

Gnomad OTH exome AF: 0.0796

GnomAD4 exome AF: 0.0736 AC: 107547 AN: 1461692 Hom.: 4364 Cov.: 33 AF XY: 0.0745 AC XY: 54179 AN XY: 727166

African (AFR) AF: 0.0197 AC: 660 AN: 33480

American (AMR) AF: 0.0568 AC: 2541 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2666 AN: 26136

East Asian (EAS) AF: 0.172 AC: 6844 AN: 39698

South Asian (SAS) AF: 0.0987 AC: 8514 AN: 86254

European-Finnish (FIN) AF: 0.0875 AC: 4666 AN: 53354

Middle Eastern (MID) AF: 0.0732 AC: 422 AN: 5768

European-Non Finnish (NFE) AF: 0.0685 AC: 76199 AN: 1111890

Other (OTH) AF: 0.0834 AC: 5035 AN: 60390

GnomAD4 genome AF: 0.0634 AC: 9652 AN: 152276 Hom.: 373 Cov.: 32 AF XY: 0.0654 AC XY: 4866 AN XY: 74446

African (AFR) AF: 0.0243 AC: 1011 AN: 41576

American (AMR) AF: 0.0556 AC: 851 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 413 AN: 3472

East Asian (EAS) AF: 0.165 AC: 849 AN: 5158

South Asian (SAS) AF: 0.0991 AC: 478 AN: 4822

European-Finnish (FIN) AF: 0.0864 AC: 918 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0714 AC: 4857 AN: 68006

Other (OTH) AF: 0.0719 AC: 152 AN: 2114

Alfa AF: 0.0692 Hom.: 1208

Bravo AF: 0.0596

Asia WGS AF: 0.117 AC: 405 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.066
DANN	Benign	0.65
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs5564; hg19: chr16-55725975; COSMIC: COSV54913176;