16-55696212-A-C

Variant names:

• chr16-55696212-A-C
• rs5568
• NM_001172501.3:c.1148-13A>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001172501.3(SLC6A2):​c.1148-13A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 1,504,612 control chromosomes in the GnomAD database, including 81,975 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 0.28 (6631 hom., cov: 32)
  • Exomes 𝑓: 0.33 (75344 hom.)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.843
• Publications: 26 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A2	NM_001172501.3	c.1148-13A>C		intron_variant	Intron 8 of 14	ENST00000568943.6	NP_001165972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A2	ENST00000568943.6	c.1148-13A>C		intron_variant	Intron 8 of 14	1	NM_001172501.3	ENSP00000457473.1

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41893 AN: 151962 Hom.: 6629 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.290

GnomAD2 exomes AF: 0.320 AC: 80507 AN: 251196 AF XY: 0.326

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.389

Gnomad EAS exome AF: 0.275

Gnomad FIN exome AF: 0.358

Gnomad NFE exome AF: 0.339

Gnomad OTH exome AF: 0.341

GnomAD4 exome AF: 0.329 AC: 445113 AN: 1352532 Hom.: 75344 Cov.: 21 AF XY: 0.331 AC XY: 224874 AN XY: 679308

African (AFR) AF: 0.102 AC: 3187 AN: 31358

American (AMR) AF: 0.326 AC: 14544 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 10019 AN: 25474

East Asian (EAS) AF: 0.313 AC: 12282 AN: 39200

South Asian (SAS) AF: 0.333 AC: 27945 AN: 84042

European-Finnish (FIN) AF: 0.359 AC: 19139 AN: 53378

Middle Eastern (MID) AF: 0.362 AC: 2012 AN: 5552

European-Non Finnish (NFE) AF: 0.334 AC: 337923 AN: 1012282

Other (OTH) AF: 0.319 AC: 18062 AN: 56674

GnomAD4 genome AF: 0.276 AC: 41903 AN: 152080 Hom.: 6631 Cov.: 32 AF XY: 0.277 AC XY: 20614 AN XY: 74334

African (AFR) AF: 0.108 AC: 4480 AN: 41510

American (AMR) AF: 0.329 AC: 5036 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1339 AN: 3468

East Asian (EAS) AF: 0.285 AC: 1476 AN: 5174

South Asian (SAS) AF: 0.333 AC: 1603 AN: 4820

European-Finnish (FIN) AF: 0.360 AC: 3806 AN: 10564

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.340 AC: 23105 AN: 67940

Other (OTH) AF: 0.296 AC: 624 AN: 2110

Alfa AF: 0.324 Hom.: 28995

Bravo AF: 0.267

Asia WGS AF: 0.292 AC: 1015 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	6.1
DANN	Benign	0.87
PhyloP100		-0.84
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: rs5568; hg19: chr16-55730124; COSMIC: COSV54915651; COSMIC: COSV54915651;