chr10-117279248-C-A

Variant names:

• chr10-117279248-C-A
• rs363238
• NM_173791.5:c.*4020G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173791.5(PDZD8):​c.*4020G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 151,978 control chromosomes in the GnomAD database, including 1,969 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (1969 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: PDZD8 NM_173791.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.196
• Publications: 2 publications found

Genes affected

PDZD8 (HGNC:26974): (PDZ domain containing 8) Predicted to enable lipid binding activity and metal ion binding activity. Involved in several processes, including mitochondrial calcium ion homeostasis; mitochondrion-endoplasmic reticulum membrane tethering; and regulation of cell morphogenesis. Located in endoplasmic reticulum membrane and mitochondria-associated endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173791.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD8	NM_173791.5	MANE Select	c.*4020G>T		3_prime_UTR	Exon 5 of 5	NP_776152.1
	SLC18A2	NM_003054.6	MANE Select	c.*1982C>A		3_prime_UTR	Exon 16 of 16	NP_003045.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD8	ENST00000334464.7	TSL:1 MANE Select	c.*4020G>T		3_prime_UTR	Exon 5 of 5	ENSP00000334642.5
	SLC18A2	ENST00000644641.2	MANE Select	c.*1982C>A		3_prime_UTR	Exon 16 of 16	ENSP00000496339.1
	SLC18A2	ENST00000497497.1	TSL:2	n.3943C>A		non_coding_transcript_exon	Exon 15 of 15

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22549 AN: 151860 Hom.: 1965 Cov.: 33

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.153

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.148 AC: 22568 AN: 151978 Hom.: 1969 Cov.: 33 AF XY: 0.155 AC XY: 11548 AN XY: 74290

African (AFR) AF: 0.146 AC: 6061 AN: 41446

American (AMR) AF: 0.210 AC: 3202 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 503 AN: 3468

East Asian (EAS) AF: 0.408 AC: 2103 AN: 5160

South Asian (SAS) AF: 0.220 AC: 1060 AN: 4814

European-Finnish (FIN) AF: 0.139 AC: 1462 AN: 10542

Middle Eastern (MID) AF: 0.202 AC: 59 AN: 292

European-Non Finnish (NFE) AF: 0.114 AC: 7760 AN: 67980

Other (OTH) AF: 0.151 AC: 319 AN: 2106

Alfa AF: 0.141 Hom.: 720

Bravo AF: 0.153

Asia WGS AF: 0.310 AC: 1076 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.3
DANN	Benign	0.52
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs363238; hg19: chr10-119038759;