16-55695212-T-C

Variant names:

• chr16-55695212-T-C
• rs2279805
• NM_001172501.3:c.1023-66T>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.1023-66T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 1,600,988 control chromosomes in the GnomAD database, including 186,087 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 0.45 (16195 hom., cov: 34)
  • Exomes 𝑓: 0.48 (169892 hom.)
• Consequence: SLC6A2 NM_001172501.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.94
• Publications: 14 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A2	NM_001172501.3	c.1023-66T>C		intron_variant	Intron 7 of 14	ENST00000568943.6	NP_001165972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A2	ENST00000568943.6	c.1023-66T>C		intron_variant	Intron 7 of 14	1	NM_001172501.3	ENSP00000457473.1

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68953 AN: 151956 Hom.: 16190 Cov.: 34

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.435

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.575

Gnomad EAS AF: 0.727

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.482

GnomAD4 exome AF: 0.480 AC: 695337 AN: 1448914 Hom.: 169892 AF XY: 0.483 AC XY: 348403 AN XY: 721580

African (AFR) AF: 0.334 AC: 11120 AN: 33256

American (AMR) AF: 0.481 AC: 21483 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 14809 AN: 26048

East Asian (EAS) AF: 0.748 AC: 29656 AN: 39642

South Asian (SAS) AF: 0.543 AC: 46701 AN: 86014

European-Finnish (FIN) AF: 0.478 AC: 24561 AN: 51384

Middle Eastern (MID) AF: 0.535 AC: 3048 AN: 5694

European-Non Finnish (NFE) AF: 0.467 AC: 514381 AN: 1102222

Other (OTH) AF: 0.493 AC: 29578 AN: 59976

GnomAD4 genome AF: 0.454 AC: 68976 AN: 152074 Hom.: 16195 Cov.: 34 AF XY: 0.456 AC XY: 33882 AN XY: 74324

African (AFR) AF: 0.341 AC: 14154 AN: 41480

American (AMR) AF: 0.492 AC: 7518 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 1996 AN: 3472

East Asian (EAS) AF: 0.727 AC: 3745 AN: 5148

South Asian (SAS) AF: 0.540 AC: 2603 AN: 4816

European-Finnish (FIN) AF: 0.474 AC: 5021 AN: 10588

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.477 AC: 32388 AN: 67968

Other (OTH) AF: 0.486 AC: 1026 AN: 2110

Alfa AF: 0.457 Hom.: 2623

Bravo AF: 0.453

Asia WGS AF: 0.604 AC: 2098 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0060
DANN	Benign	0.47
PhyloP100		-1.9
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: rs2279805; hg19: chr16-55729124; COSMIC: COSV107271340; COSMIC: COSV107271340;