16-55683165-T-C

Variant names:

• chr16-55683165-T-C
• rs1814270
• NM_001172501.3:c.645-1978T>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.645-1978T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 152,102 control chromosomes in the GnomAD database, including 10,147 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 0.34 (10147 hom., cov: 32)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.751
• Publications: 8 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A2	NM_001172501.3	c.645-1978T>C		intron_variant	Intron 4 of 14	ENST00000568943.6	NP_001165972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A2	ENST00000568943.6	c.645-1978T>C		intron_variant	Intron 4 of 14	1	NM_001172501.3	ENSP00000457473.1

Frequencies

GnomAD3 genomes AF: 0.342 AC: 52038 AN: 151984 Hom.: 10148 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.529

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.471

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.364

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

GnomAD4 genome AF: 0.342 AC: 52060 AN: 152102 Hom.: 10147 Cov.: 32 AF XY: 0.343 AC XY: 25476 AN XY: 74332

African (AFR) AF: 0.146 AC: 6049 AN: 41534

American (AMR) AF: 0.387 AC: 5914 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 1838 AN: 3472

East Asian (EAS) AF: 0.344 AC: 1780 AN: 5168

South Asian (SAS) AF: 0.471 AC: 2274 AN: 4826

European-Finnish (FIN) AF: 0.420 AC: 4420 AN: 10532

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28644 AN: 67972

Other (OTH) AF: 0.363 AC: 764 AN: 2104

Alfa AF: 0.399 Hom.: 23693

Bravo AF: 0.329

Asia WGS AF: 0.391 AC: 1361 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.4
DANN	Benign	0.46
PhyloP100		-0.75
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: rs1814270; hg19: chr16-55717077;