Genetic Variant NM_003054.6:c.1160C>A (chr10-117267710-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_003054.6(SLC18A2):c.1160C>A(p.Pro387Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P387L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SLC18A2
NM_003054.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.78

Publications

0 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:

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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;

PM5

Other missense variant is known to change same aminoacid residue: 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC18A2	NM_003054.6 link	c.1160C>A	p.Pro387Gln	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>A	p.Pro387Gln	missense_variant	Exon 13 of 16		NM_003054.6	ENSP00000496339.1	Q05940-1
SLC18A2	ENST00000497497.1 link	n.1576C>A		non_coding_transcript_exon_variant	Exon 12 of 15	2
ENSG00000277879	ENST00000614747.1 link	n.959G>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1414152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

697856

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32984

American (AMR)

AF:

0.00

AC:

AN:

44286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25096

East Asian (EAS)

AF:

0.00

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:

9.30e-7

AC:

AN:

1075240

Other (OTH)

AF:

0.00

AC:

AN:

57764

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

D;D

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;D

M_CAP

Benign

0.052

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Uncertain

-0.032

MutationAssessor

Pathogenic

3.4

M;M

PhyloP100

7.8

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-7.4

D;.

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

1.0

D;D

Vest4

0.91

MutPred

0.72

Loss of stability (P = 0.1142);Loss of stability (P = 0.1142);

MVP

0.63

MPC

1.0

ClinPred

1.0

GERP RS

5.6

Varity_R

0.86

gMVP

0.88

Mutation Taster

=31/69

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over