10-117267710-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_003054.6(SLC18A2):c.1160C>T(p.Pro387Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000354 in 1,414,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P387P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

SLC18A2
NM_003054.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.78

Publications

16 publications found

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 Gene-Disease associations (from GenCC):

brain dopamine-serotonin vesicular transport disease
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P
parkinsonism-dystonia, infantile, 2
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
schizophrenia
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

SLC18A2 links:

ENSG00000277879 (HGNC:):

ENSG00000277879 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

PP5

Variant 10-117267710-C-T is Pathogenic according to our data. Variant chr10-117267710-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548130.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC18A2	NM_003054.6 link	c.1160C>T	p.Pro387Leu	missense_variant	Exon 13 of 16	ENST00000644641.2	NP_003045.2	Q05940-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC18A2	ENST00000644641.2 link	c.1160C>T	p.Pro387Leu	missense_variant	Exon 13 of 16		NM_003054.6	ENSP00000496339.1	Q05940-1
SLC18A2	ENST00000497497.1 link	n.1576C>T		non_coding_transcript_exon_variant	Exon 12 of 15	2
ENSG00000277879	ENST00000614747.1 link	n.959G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251372

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000354

AC:

AN:

1414152

Hom.:

Cov.:

AF XY:

0.00000430

AC XY:

AN XY:

697856

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32984

American (AMR)

AF:

0.0000226

AC:

AN:

44286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25096

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38884

South Asian (SAS)

AF:

0.00

AC:

AN:

82288

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52084

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5526

European-Non Finnish (NFE)

AF:

0.00000279

AC:

AN:

1075240

Other (OTH)

AF:

0.00

AC:

AN:

57764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Brain dopamine-serotonin vesicular transport disease

Pathogenic:2

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 11, 2023

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

.;D

M_CAP

Benign

0.049

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Benign

-0.37

MutationAssessor

Pathogenic

3.0

M;M

PhyloP100

7.8

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-9.1

D;.

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

1.0

D;D

Vest4

0.96

MutPred

0.75

Loss of catalytic residue at P387 (P = 0.0494);Loss of catalytic residue at P387 (P = 0.0494);

MVP

0.70

MPC

0.40

ClinPred

1.0

GERP RS

5.6

Varity_R

0.79

gMVP

0.94

Mutation Taster

=26/74

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over