rs5564

Positions:

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

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000568943.6(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 ENST00000568943.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
SLC6A2	NM_001172501.3	c.918+11A>G		intron_variant		ENST00000568943.6	NP_001165972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A2	ENST00000568943.6	c.918+11A>G		intron_variant		1	NM_001172501.3	ENSP00000457473	P1

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

GnomAD3 exomes AF: 0.0783 AC: 19658 AN: 251150 Hom.: 927 AF XY: 0.0807 AC XY: 10950 AN XY: 135742

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 SAS exome AF: 0.0986

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

Gnomad4 AFR exome AF: 0.0197

Gnomad4 AMR exome AF: 0.0568

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.172

Gnomad4 SAS exome AF: 0.0987

Gnomad4 FIN exome AF: 0.0875

Gnomad4 NFE exome AF: 0.0685

Gnomad4 OTH exome AF: 0.0834

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

Gnomad4 AFR AF: 0.0243

Gnomad4 AMR AF: 0.0556

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.0991

Gnomad4 FIN AF: 0.0864

Gnomad4 NFE AF: 0.0714

Gnomad4 OTH AF: 0.0719

Alfa AF: 0.0691 Hom.: 437

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs5564; hg19: chr16-55725975; COSMIC: COSV54913176;