Genetic Variant PDE8A:p.Arg368Gly (chr15-85109118-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002605.3(PDE8A):c.1102C>G(p.Arg368Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,850 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R368C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PDE8A
NM_002605.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.13

Publications

0 publications found

Variant links:

Genes affected

PDE8A (HGNC:8793): (phosphodiesterase 8A) The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE8 subfamily. This PDE hydrolyzes the second messenger, cAMP, which is a regulator and mediator of a number of cellular responses to extracellular signals. Thus, by regulating the cellular concentration of cAMP, this protein plays a key role in many important physiological processes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2011]

PDE8A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002605.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDE8A	NM_002605.3	MANE Select	c.1102C>G	p.Arg368Gly	missense	Exon 12 of 22	NP_002596.1	O60658-1
PDE8A	NM_173454.1		c.964C>G	p.Arg322Gly	missense	Exon 11 of 21	NP_775656.1	O60658-2
PDE8A	NM_001243137.2		c.886C>G	p.Arg296Gly	missense	Exon 12 of 22	NP_001230066.1	O60658-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDE8A	ENST00000394553.6	TSL:1 MANE Select	c.1102C>G	p.Arg368Gly	missense	Exon 12 of 22	ENSP00000378056.1	O60658-1
PDE8A	ENST00000310298.8	TSL:1	c.1102C>G	p.Arg368Gly	missense	Exon 13 of 23	ENSP00000311453.4	O60658-1
PDE8A	ENST00000339708.9	TSL:1	c.964C>G	p.Arg322Gly	missense	Exon 11 of 21	ENSP00000340679.5	O60658-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1454850

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33342

American (AMR)

AF:

0.0000224

AC:

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26034

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39638

South Asian (SAS)

AF:

0.00

AC:

AN:

85818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106194

Other (OTH)

AF:

0.00

AC:

AN:

60102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.22

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.72

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.63

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.6

PhyloP100

2.1

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.38

Sift

Uncertain

0.017

Sift4G

Benign

0.22

Polyphen

0.80

Vest4

0.67

MutPred

0.41

Gain of ubiquitination at K363 (P = 0.0211)

MVP

0.60

MPC

0.63

ClinPred

0.54

GERP RS

2.1

Varity_R

0.058

gMVP

0.47

Mutation Taster

=70/30

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over