rs363279

Variant names:

• chr10-117277114-T-C
• rs363279
• NM_003054.6:c.1441-48T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003054.6(SLC18A2):​c.1441-48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,077,238 control chromosomes in the GnomAD database, including 8,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1143 hom., cov: 32)
  • Exomes 𝑓: 0.11 (7056 hom.)
• Consequence: SLC18A2 NM_003054.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.127
• Publications: 4 publications found

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]

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]

PDZD8 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with autism and dysmorphic facies

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-117277114-T-C is Benign according to our data. Variant chr10-117277114-T-C is described in ClinVar as Benign. ClinVar VariationId is 1283694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC18A2	NM_003054.6	c.1441-48T>C		intron_variant	Intron 15 of 15	ENST00000644641.2	NP_003045.2
PDZD8	NM_173791.5	c.*6154A>G		downstream_gene_variant		ENST00000334464.7	NP_776152.1
PDZD8	XM_005269518.5	c.*6154A>G		downstream_gene_variant			XP_005269575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC18A2	ENST00000644641.2	c.1441-48T>C		intron_variant	Intron 15 of 15		NM_003054.6	ENSP00000496339.1
SLC18A2	ENST00000497497.1	n.1857-48T>C		intron_variant	Intron 14 of 14	2
PDZD8	ENST00000334464.7	c.*6154A>G		downstream_gene_variant		1	NM_173791.5	ENSP00000334642.5

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16088 AN: 152144 Hom.: 1140 Cov.: 32

Gnomad AFR AF: 0.0848

Gnomad AMI AF: 0.0330

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.0503

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.0879

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.130 AC: 26649 AN: 205080 AF XY: 0.128

Gnomad AFR exome AF: 0.0847

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.352

Gnomad FIN exome AF: 0.0532

Gnomad NFE exome AF: 0.0888

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.108 AC: 99844 AN: 924976 Hom.: 7056 Cov.: 12 AF XY: 0.109 AC XY: 52299 AN XY: 479904

African (AFR) AF: 0.0839 AC: 1782 AN: 21240

American (AMR) AF: 0.202 AC: 6978 AN: 34486

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 2503 AN: 20662

East Asian (EAS) AF: 0.342 AC: 12140 AN: 35524

South Asian (SAS) AF: 0.157 AC: 10597 AN: 67374

European-Finnish (FIN) AF: 0.0552 AC: 2767 AN: 50084

Middle Eastern (MID) AF: 0.173 AC: 642 AN: 3708

European-Non Finnish (NFE) AF: 0.0883 AC: 57404 AN: 649836

Other (OTH) AF: 0.120 AC: 5031 AN: 42062

GnomAD4 genome AF: 0.106 AC: 16101 AN: 152262 Hom.: 1143 Cov.: 32 AF XY: 0.110 AC XY: 8181 AN XY: 74454

African (AFR) AF: 0.0847 AC: 3518 AN: 41538

American (AMR) AF: 0.182 AC: 2777 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 402 AN: 3470

East Asian (EAS) AF: 0.341 AC: 1766 AN: 5182

South Asian (SAS) AF: 0.167 AC: 808 AN: 4826

European-Finnish (FIN) AF: 0.0503 AC: 534 AN: 10622

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.0879 AC: 5981 AN: 68016

Other (OTH) AF: 0.112 AC: 236 AN: 2116

Alfa AF: 0.0949 Hom.: 299

Bravo AF: 0.115

Asia WGS AF: 0.249 AC: 866 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.6
DANN	Benign	0.81
PhyloP100		-0.13
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: rs363279; hg19: chr10-119036625; COSMIC: COSV53689272; COSMIC: COSV53689272;