16-55656758-G-C

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.64G>C(p.Glu22Gln) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A2 NM_001172501.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

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 where missense usually causes diseases, SLC6A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.07345012).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A2	NM_001172501.3	c.64G>C	p.Glu22Gln	missense_variant	2/15	ENST00000568943.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A2	ENST00000568943.6	c.64G>C	p.Glu22Gln	missense_variant	2/15	1	NM_001172501.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2023

The c.64G>C (p.E22Q) alteration is located in exon 1 (coding exon 1) of the SLC6A2 gene. This alteration results from a G to C substitution at nucleotide position 64, causing the glutamic acid (E) at amino acid position 22 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	15
Dann	Benign	0.85
DEOGEN2	Benign	0.10	T;.;T;.;T;T;.;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.19	N
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.073	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	L;.;.;.;L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.42	N;N;N;N;N;N;N;N
Sift	Benign	0.32	T;T;T;T;T;T;T;T
Sift4G	Benign	0.46	T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;B;.;.;.
Vest4		0.15
MutPred		0.22		Gain of MoRF binding (P = 0.0625);Gain of MoRF binding (P = 0.0625);Gain of MoRF binding (P = 0.0625);Gain of MoRF binding (P = 0.0625);Gain of MoRF binding (P = 0.0625);Gain of MoRF binding (P = 0.0625);Gain of MoRF binding (P = 0.0625);Gain of MoRF binding (P = 0.0625);
MVP		0.68
MPC		0.72
ClinPred		0.033	T
GERP RS		0.62
Varity_R		0.077
gMVP		0.31

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: rs1964462842; hg19: chr16-55690670;