Genetic Variant NM_002605.3:c.14C>A (chr15-84982176-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_002605.3(PDE8A):c.14C>A(p.Pro5Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,326,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. P5R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

PDE8A
NM_002605.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.959

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35988683).

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.14C>A	p.Pro5Gln	missense	Exon 1 of 22	NP_002596.1	O60658-1
PDE8A	NM_173454.1		c.14C>A	p.Pro5Gln	missense	Exon 1 of 21	NP_775656.1	O60658-2
PDE8A	NM_001243137.2		c.-31+1491C>A		intron	N/A	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.14C>A	p.Pro5Gln	missense	Exon 1 of 22	ENSP00000378056.1	O60658-1
PDE8A	ENST00000310298.8	TSL:1	c.14C>A	p.Pro5Gln	missense	Exon 2 of 23	ENSP00000311453.4	O60658-1
PDE8A	ENST00000339708.9	TSL:1	c.14C>A	p.Pro5Gln	missense	Exon 1 of 21	ENSP00000340679.5	O60658-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000151

AC:

AN:

1326360

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

657370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26646

American (AMR)

AF:

0.00

AC:

AN:

27456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22518

East Asian (EAS)

AF:

0.00

AC:

AN:

28908

South Asian (SAS)

AF:

0.00

AC:

AN:

73102

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33392

Middle Eastern (MID)

AF:

0.000253

AC:

AN:

3960

European-Non Finnish (NFE)

AF:

9.47e-7

AC:

AN:

1056066

Other (OTH)

AF:

0.00

AC:

AN:

54312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

0.28

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.42

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.72

MetaRNN

Benign

0.36

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.6

PhyloP100

0.96

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.24

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0060

Polyphen

0.98

Vest4

0.26

MutPred

0.41

Gain of MoRF binding (P = 0.0838)

MVP

0.41

MPC

0.18

ClinPred

0.72

GERP RS

-0.44

PromoterAI

-0.0079

Neutral

(source)

Varity_R

0.17

gMVP

0.46

Mutation Taster

=89/11

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