10-117241736-AGCCGCCGCTC-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_003054.6(SLC18A2):c.46_55del(p.Arg16GlyfsTer78) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC18A2 NM_003054.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.26

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-117241736-AGCCGCCGCTC-A is Pathogenic according to our data. Variant chr10-117241736-AGCCGCCGCTC-A is described in ClinVar as [Pathogenic]. Clinvar id is 2793810.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC18A2	NM_003054.6	c.46_55del	p.Arg16GlyfsTer78	frameshift_variant	2/16	ENST00000644641.2
SLC18A2-AS1	NR_184309.1	n.113+139_113+148del		intron_variant, non_coding_transcript_variant
SLC18A2-AS1	NR_184310.1	n.151_160del		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC18A2	ENST00000644641.2	c.46_55del	p.Arg16GlyfsTer78	frameshift_variant	2/16		NM_003054.6	P1
SLC18A2-AS1	ENST00000425264.2	n.152_161del		non_coding_transcript_exon_variant	2/3	3
SLC18A2	ENST00000497497.1	n.189_198del		non_coding_transcript_exon_variant	2/15	2
SLC18A2-AS1	ENST00000691914.2	n.113+139_113+148del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 31, 2022

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with SLC18A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg16Glyfs*78) in the SLC18A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC18A2 are known to be pathogenic (PMID: 26539891, 31618753). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-119001247;