Genetic Variant PDE9A:c.218+139C>G (chr21-42688133-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002606.3(PDE9A):c.218+139C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 730,018 control chromosomes in the GnomAD database, including 10,552 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 ( 1948 hom., cov: 32)

Exomes 𝑓: 0.16 ( 8604 hom. )

Consequence

PDE9A
NM_002606.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.119

Publications

2 publications found

Variant links:

Genes affected

PDE9A (HGNC:8795): (phosphodiesterase 9A) The protein encoded by this gene catalyzes the hydrolysis of cAMP and cGMP to their corresponding monophosphates. The encoded protein plays a role in signal transduction by regulating the intracellular concentration of these cyclic nucleotides. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PDE9A links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002606.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PDE9A	NM_002606.3	MANE Select	c.218+139C>G	intron	N/A	NP_002597.1
PDE9A	NM_001001583.2		c.140+1871C>G	intron	N/A	NP_001001583.1
PDE9A	NM_001001582.2		c.95+139C>G	intron	N/A	NP_001001582.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PDE9A	ENST00000291539.11	TSL:1 MANE Select	c.218+139C>G	intron	N/A	ENSP00000291539.6
PDE9A	ENST00000328862.10	TSL:1	c.140+1871C>G	intron	N/A	ENSP00000328699.6
PDE9A	ENST00000398225.7	TSL:1	c.95+139C>G	intron	N/A	ENSP00000381281.3

Frequencies

GnomAD3 genomes

AF:

0.155

AC:

23505

AN:

152064

Hom.:

1950

Cov.:

show subpopulations

Gnomad AFR

AF:

0.132

Gnomad AMI

AF:

0.121

Gnomad AMR

AF:

0.116

Gnomad ASJ

AF:

0.230

Gnomad EAS

AF:

0.340

Gnomad SAS

AF:

0.145

Gnomad FIN

AF:

0.147

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.161

Gnomad OTH

AF:

0.171

GnomAD4 exome

AF:

0.164

AC:

94642

AN:

577836

Hom.:

8604

AF XY:

0.164

AC XY:

50121

AN XY:

306306

show subpopulations

African (AFR)

AF:

0.133

AC:

2160

AN:

16274

American (AMR)

AF:

0.0840

AC:

2770

AN:

32976

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

4218

AN:

18220

East Asian (EAS)

AF:

0.333

AC:

10667

AN:

31990

South Asian (SAS)

AF:

0.135

AC:

8082

AN:

59934

European-Finnish (FIN)

AF:

0.147

AC:

4865

AN:

33010

Middle Eastern (MID)

AF:

0.181

AC:

722

AN:

3986

European-Non Finnish (NFE)

AF:

0.160

AC:

55986

AN:

350344

Other (OTH)

AF:

0.166

AC:

5172

AN:

31102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

3906

7812

11719

15625

19531

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

664

1328

1992

2656

3320

<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:

0.155

AC:

23524

AN:

152182

Hom.:

1948

Cov.:

AF XY:

0.154

AC XY:

11471

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.132

AC:

5482

AN:

41526

American (AMR)

AF:

0.116

AC:

1776

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

796

AN:

3468

East Asian (EAS)

AF:

0.340

AC:

1755

AN:

5166

South Asian (SAS)

AF:

0.144

AC:

694

AN:

4822

European-Finnish (FIN)

AF:

0.147

AC:

1554

AN:

10596

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.161

AC:

10937

AN:

68002

Other (OTH)

AF:

0.175

AC:

369

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1022

2045

3067

4090

5112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

264

528

792

1056

1320

<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:

0.0661

Hom.:

Bravo

AF:

0.155

Asia WGS

AF:

0.206

AC:

717

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

2.2

(source)

DANN

Benign

0.42

PhyloP100

-0.12

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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