10-117241742-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003054.6(SLC18A2):c.49C>T(p.Arg17Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000492 in 1,609,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R17R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00051 ( 0 hom. )

Consequence

SLC18A2
NM_003054.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.35

Variant links:

Genes affected

SLC18A2 (HGNC:10935): (solute carrier family 18 member A2) This gene encodes an transmembrane protein that functions as an ATP-dependent transporter of monoamines, such as dopamine, norepinephrine, serotonin, and histamine. This protein transports amine neurotransmitters into synaptic vesicles. Polymorphisms in this gene may be associated with schizophrenia, bipolar disorder, and other neurological/psychiatric ailments. [provided by RefSeq, Jun 2018]

SLC18A2 links:

SLC18A2-AS1 (HGNC:55843): (SLC18A2 antisense RNA 1)

SLC18A2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.130317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC18A2	NM_003054.6 linkuse as main transcript	c.49C>T	p.Arg17Cys	missense_variant	2/16	ENST00000644641.2
SLC18A2-AS1	NR_184309.1 linkuse as main transcript	n.113+143G>A		intron_variant, non_coding_transcript_variant
SLC18A2-AS1	NR_184310.1 linkuse as main transcript	n.155G>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC18A2	ENST00000644641.2 linkuse as main transcript	c.49C>T	p.Arg17Cys	missense_variant	2/16		NM_003054.6	P1	Q05940-1
SLC18A2-AS1	ENST00000425264.2 linkuse as main transcript	n.156G>A		non_coding_transcript_exon_variant	2/3	3
SLC18A2	ENST00000497497.1 linkuse as main transcript	n.192C>T		non_coding_transcript_exon_variant	2/15	2
SLC18A2-AS1	ENST00000691914.2 linkuse as main transcript	n.113+143G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000266

AC:

AN:

237006

Hom.:

AF XY:

0.000224

AC XY:

AN XY:

129536

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000332

Gnomad FIN exome

AF:

0.0000481

Gnomad NFE exome

AF:

0.000577

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.000512

AC:

747

AN:

1457640

Hom.:

Cov.:

AF XY:

0.000452

AC XY:

328

AN XY:

724980

show subpopulations

Gnomad4 AFR exome

AF:

0.0000602

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000115

Gnomad4 NFE exome

AF:

0.000594

Gnomad4 OTH exome

AF:

0.00130

GnomAD4 genome

AF:

0.000296

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000363

Hom.:

Bravo

AF:

0.000332

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000365

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2023

The c.49C>T (p.R17C) alteration is located in exon 2 (coding exon 1) of the SLC18A2 gene. This alteration results from a C to T substitution at nucleotide position 49, causing the arginine (R) at amino acid position 17 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 17 of the SLC18A2 protein (p.Arg17Cys). This variant is present in population databases (rs148348449, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with SLC18A2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.27

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.94

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.13

T;T

MetaSVM

Uncertain

-0.088

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.8

N;.

REVEL

Uncertain

0.34

Sift

Benign

0.032

D;.

Sift4G

Uncertain

0.033

D;.

Polyphen

0.59

P;P

Vest4

0.25

MVP

0.45

MPC

0.67

ClinPred

0.19

GERP RS

5.2

Varity_R

0.25

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over