NM_001172501.3:c.1830+66C>T

Variant names:

• chr16-55702000-C-T
• rs2242447
• NM_001172501.3:c.1830+66C>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.1830+66C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 1,231,124 control chromosomes in the GnomAD database, including 252,707 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 0.53 (24372 hom., cov: 33)
  • Exomes 𝑓: 0.64 (228335 hom.)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36
• Publications: 32 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: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

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 (AMR) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172501.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	NM_001172501.3	MANE Select	c.1830+66C>T		intron	N/A	NP_001165972.1	P23975-1
	SLC6A2	NM_001172504.1		c.1830+66C>T		intron	N/A	NP_001165975.1	P23975-2
	SLC6A2	NM_001043.3		c.1830+66C>T		intron	N/A	NP_001034.1	P23975-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	ENST00000568943.6	TSL:1 MANE Select	c.1830+66C>T		intron	N/A	ENSP00000457473.1	P23975-1
	SLC6A2	ENST00000379906.6	TSL:1	c.1830+66C>T		intron	N/A	ENSP00000369237.2	P23975-1
	SLC6A2	ENST00000219833.13	TSL:5	c.1830+66C>T		intron	N/A	ENSP00000219833.8	P23975-2

Frequencies

GnomAD3 genomes AF: 0.533 AC: 81002 AN: 151978 Hom.: 24362 Cov.: 33

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.571

Gnomad SAS AF: 0.474

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.555

GnomAD4 exome AF: 0.643 AC: 693503 AN: 1079028 Hom.: 228335 AF XY: 0.638 AC XY: 353618 AN XY: 554154

African (AFR) AF: 0.217 AC: 5648 AN: 26038

American (AMR) AF: 0.740 AC: 32530 AN: 43948

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 16293 AN: 23726

East Asian (EAS) AF: 0.598 AC: 22676 AN: 37924

South Asian (SAS) AF: 0.487 AC: 38283 AN: 78622

European-Finnish (FIN) AF: 0.598 AC: 31688 AN: 52992

Middle Eastern (MID) AF: 0.592 AC: 2986 AN: 5042

European-Non Finnish (NFE) AF: 0.674 AC: 514334 AN: 763086

Other (OTH) AF: 0.610 AC: 29065 AN: 47650

GnomAD4 genome AF: 0.533 AC: 81020 AN: 152096 Hom.: 24372 Cov.: 33 AF XY: 0.529 AC XY: 39345 AN XY: 74352

African (AFR) AF: 0.231 AC: 9599 AN: 41490

American (AMR) AF: 0.676 AC: 10325 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 2330 AN: 3472

East Asian (EAS) AF: 0.571 AC: 2936 AN: 5140

South Asian (SAS) AF: 0.473 AC: 2281 AN: 4820

European-Finnish (FIN) AF: 0.589 AC: 6231 AN: 10584

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.668 AC: 45443 AN: 67992

Other (OTH) AF: 0.558 AC: 1178 AN: 2110

Alfa AF: 0.627 Hom.: 40197

Bravo AF: 0.528

Asia WGS AF: 0.473 AC: 1645 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.59
DANN	Benign	0.80
PhyloP100		-1.4
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: rs2242447; hg19: chr16-55735912; COSMIC: COSV54920545; COSMIC: COSV54920545;