16-55682638-T-C

Variant names:

• chr16-55682638-T-C
• rs3785152
• NM_001172501.3:c.645-2505T>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.645-2505T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.868 in 152,230 control chromosomes in the GnomAD database, including 57,601 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 0.87 (57601 hom., cov: 32)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.22
• Publications: 13 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.892 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A2	NM_001172501.3	c.645-2505T>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.645-2505T>C		intron_variant	Intron 4 of 14	1	NM_001172501.3	ENSP00000457473.1

Frequencies

GnomAD3 genomes AF: 0.868 AC: 131989 AN: 152112 Hom.: 57562 Cov.: 32

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.925

Gnomad AMR AF: 0.899

Gnomad ASJ AF: 0.894

Gnomad EAS AF: 0.871

Gnomad SAS AF: 0.865

Gnomad FIN AF: 0.932

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.898

Gnomad OTH AF: 0.868

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

GnomAD4 genome AF: 0.868 AC: 132080 AN: 152230 Hom.: 57601 Cov.: 32 AF XY: 0.871 AC XY: 64832 AN XY: 74422

African (AFR) AF: 0.786 AC: 32609 AN: 41500

American (AMR) AF: 0.899 AC: 13767 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.894 AC: 3104 AN: 3472

East Asian (EAS) AF: 0.871 AC: 4508 AN: 5174

South Asian (SAS) AF: 0.865 AC: 4173 AN: 4824

European-Finnish (FIN) AF: 0.932 AC: 9881 AN: 10606

Middle Eastern (MID) AF: 0.925 AC: 272 AN: 294

European-Non Finnish (NFE) AF: 0.898 AC: 61086 AN: 68030

Other (OTH) AF: 0.869 AC: 1838 AN: 2114

Alfa AF: 0.894 Hom.: 103355

Bravo AF: 0.863

Asia WGS AF: 0.878 AC: 3051 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.27
DANN	Benign	0.65
PhyloP100		-4.2
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: rs3785152; hg19: chr16-55716550;