16-55692009-A-G

Variant names:

• chr16-55692009-A-G
• rs5563
• NM_001172501.3:c.875A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001172501.3(SLC6A2):​c.875A>G​(p.Asn292Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC6A2 NM_001172501.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.941
• Publications: 10 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07709578).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	NM_001172501.3	MANE Select	c.875A>G	p.Asn292Ser	missense	Exon 6 of 15	NP_001165972.1
	SLC6A2	NM_001172504.1		c.875A>G	p.Asn292Ser	missense	Exon 5 of 14	NP_001165975.1
	SLC6A2	NM_001043.3		c.875A>G	p.Asn292Ser	missense	Exon 5 of 14	NP_001034.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A2	ENST00000568943.6	TSL:1 MANE Select	c.875A>G	p.Asn292Ser	missense	Exon 6 of 15	ENSP00000457473.1
	SLC6A2	ENST00000379906.6	TSL:1	c.875A>G	p.Asn292Ser	missense	Exon 5 of 14	ENSP00000369237.2
	SLC6A2	ENST00000219833.13	TSL:5	c.875A>G	p.Asn292Ser	missense	Exon 5 of 14	ENSP00000219833.8

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.83
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.68	N
PhyloP100		0.94
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.048
Sift	Benign	0.73	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.28		Gain of disorder (P = 0.0732)
MVP		0.50
MPC		0.58
ClinPred		0.058	T
GERP RS		1.2
Varity_R		0.037
gMVP		0.19
Mutation Taster		=94/6	polymorphism

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: rs5563; hg19: chr16-55725921;