rs5563

Positions:

• chr16-55692009-A-C
• chr16-55692009-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001172501.3(SLC6A2):​c.875A>C​(p.Asn292Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A2 NM_001172501.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.941

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC6A2. . Gene score misZ 2.0193 (greater than the threshold 3.09). Trascript score misZ 3.3305 (greater than threshold 3.09). GenCC has associacion of gene with postural orthostatic tachycardia syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12576678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A2	NM_001172501.3	c.875A>C	p.Asn292Thr	missense_variant	6/15	ENST00000568943.6	NP_001165972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A2	ENST00000568943.6	c.875A>C	p.Asn292Thr	missense_variant	6/15	1	NM_001172501.3	ENSP00000457473.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.035	T;T;T;T;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.68	.;T;T;T;T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.15	N;.;N;.;N;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.030	N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.52	T;T;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;.;.
Vest4		0.24
MutPred		0.15		Gain of glycosylation at N292 (P = 0.0295);Gain of glycosylation at N292 (P = 0.0295);Gain of glycosylation at N292 (P = 0.0295);Gain of glycosylation at N292 (P = 0.0295);Gain of glycosylation at N292 (P = 0.0295);.;
MVP		0.61
MPC		0.74
ClinPred		0.13	T
GERP RS		1.2
Varity_R		0.062
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs5563; hg19: chr16-55725921;