Genetic Variant NM_003054.6:c.1441-48T>C (chr10-117277114-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.127

Publications

4 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 links:

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

PDZD8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003054.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC18A2	NM_003054.6	MANE Select	c.1441-48T>C		intron	N/A	NP_003045.2
	PDZD8	NM_173791.5	MANE Select	c.*6154A>G		downstream_gene	N/A	NP_776152.1	Q8NEN9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC18A2	ENST00000644641.2	MANE Select	c.1441-48T>C	intron	N/A	ENSP00000496339.1	Q05940-1
SLC18A2	ENST00000853677.1		c.1537-48T>C	intron	N/A	ENSP00000523736.1
SLC18A2	ENST00000853679.1		c.1534-48T>C	intron	N/A	ENSP00000523738.1

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16088

AN:

152144

Hom.:

1140

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.109

AC XY:

52299

AN XY:

479904

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

4072

8143

12215

16286

20358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1866

3732

5598

7464

9330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.106

AC:

16101

AN:

152262

Hom.:

1143

Cov.:

AF XY:

0.110

AC XY:

8181

AN XY:

74454

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0879

AC:

5981

AN:

68016

Other (OTH)

AF:

0.112

AC:

236

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

705

1410

2114

2819

3524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

190

380

570

760

950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0949

Hom.:

299

Bravo

AF:

0.115

Asia WGS

AF:

0.249

AC:

866

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

9.6

(source)

DANN

Benign

0.81

PhyloP100

-0.13

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over