10-117244052-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003054.6(SLC18A2):c.203C>T(p.Thr68Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000783 in 1,614,170 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T68M) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0042 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (2 hom.)
• Consequence: SLC18A2 NM_003054.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.261

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044593215).
• BP6: Variant 10-117244052-C-T is Benign according to our data. Variant chr10-117244052-C-T is described in ClinVar as [Benign]. Clinvar id is 717979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00422 (642/152310) while in subpopulation AFR AF= 0.0147 (609/41546). AF 95% confidence interval is 0.0137. There are 4 homozygotes in gnomad4. There are 299 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC18A2	NM_003054.6	c.203C>T	p.Thr68Ile	missense_variant	3/16	ENST00000644641.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC18A2	ENST00000644641.2	c.203C>T	p.Thr68Ile	missense_variant	3/16		NM_003054.6	P1
SLC18A2	ENST00000497497.1	n.346C>T		non_coding_transcript_exon_variant	3/15	2

Frequencies

GnomAD3 genomes AF: 0.00420 AC: 639 AN: 152192 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

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: 0.0000735

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00114 AC: 287 AN: 251440 Hom.: 1 AF XY: 0.000824 AC XY: 112 AN XY: 135914

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000425 AC: 622 AN: 1461860 Hom.: 2 Cov.: 31 AF XY: 0.000366 AC XY: 266 AN XY: 727230

Gnomad4 AFR exome AF: 0.0148

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.00422 AC: 642 AN: 152310 Hom.: 4 Cov.: 33 AF XY: 0.00401 AC XY: 299 AN XY: 74476

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.000697 Hom.: 2

Bravo AF: 0.00457

ExAC AF: 0.00148 AC: 180

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 09, 2018

- -

SLC18A2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	8.7
Dann	Benign	0.85
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.51	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.068
Sift	Benign	0.23	T;.
Sift4G	Benign	0.20	T;.
Polyphen		0.0	B;B
Vest4		0.11
MVP		0.043
MPC		0.40
ClinPred		0.0015	T
GERP RS		0.23
Varity_R		0.036
gMVP		0.40

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

Other links and lift over

dbSNP: rs137920074; hg19: chr10-119003563;