10-117241738-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003054.6(SLC18A2):c.45C>A(p.Ser15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,608,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SLC18A2
NM_003054.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.00

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06081128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC18A2	NM_003054.6 linkuse as main transcript	c.45C>A	p.Ser15Arg	missense_variant	2/16	ENST00000644641.2
SLC18A2-AS1	NR_184309.1 linkuse as main transcript	n.113+147G>T		intron_variant, non_coding_transcript_variant
SLC18A2-AS1	NR_184310.1 linkuse as main transcript	n.159G>T		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.45C>A	p.Ser15Arg	missense_variant	2/16		NM_003054.6	P1	Q05940-1
SLC18A2-AS1	ENST00000425264.2 linkuse as main transcript	n.160G>T		non_coding_transcript_exon_variant	2/3	3
SLC18A2	ENST00000497497.1 linkuse as main transcript	n.188C>A		non_coding_transcript_exon_variant	2/15	2
SLC18A2-AS1	ENST00000691914.2 linkuse as main transcript	n.113+147G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000383

AC:

AN:

234764

Hom.:

AF XY:

0.0000389

AC XY:

AN XY:

128422

show subpopulations

Gnomad AFR exome

AF:

0.000410

Gnomad AMR exome

AF:

0.0000589

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000972

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1456600

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

724348

show subpopulations

Gnomad4 AFR exome

AF:

0.000392

Gnomad4 AMR exome

AF:

0.0000674

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.000138

AC:

AN:

152016

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.000483

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000232

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000166

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

Dec 01, 2022

The c.45C>A (p.S15R) alteration is located in exon 2 (coding exon 1) of the SLC18A2 gene. This alteration results from a C to A substitution at nucleotide position 45, causing the serine (S) at amino acid position 15 to be replaced by an arginine (R). 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

Jun 18, 2022

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 15 of the SLC18A2 protein (p.Ser15Arg). This variant is present in population databases (rs371946127, 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

0.22

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.58

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.72

M_CAP

Benign

0.010

MetaRNN

Benign

0.061

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

0.84

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.4

N;.

REVEL

Benign

0.024

Sift

Benign

0.34

T;.

Sift4G

Benign

0.34

T;.

Polyphen

0.0

B;B

Vest4

0.31

MutPred

0.36

Gain of MoRF binding (P = 0.043);Gain of MoRF binding (P = 0.043);

MVP

0.043

MPC

0.41

ClinPred

0.039

GERP RS

2.3

Varity_R

0.15

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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