Genetic Variant PDE8A:p.Ser336Cys (chr15-85100169-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002605.3(PDE8A):c.1007C>G(p.Ser336Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. S336P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PDE8A
NM_002605.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.788

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09767446).

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.1007C>G	p.Ser336Cys	missense	Exon 11 of 22	NP_002596.1	O60658-1
PDE8A	NM_173454.1		c.869C>G	p.Ser290Cys	missense	Exon 10 of 21	NP_775656.1	O60658-2
PDE8A	NM_001243137.2		c.791C>G	p.Ser264Cys	missense	Exon 11 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.1007C>G	p.Ser336Cys	missense	Exon 11 of 22	ENSP00000378056.1	O60658-1
PDE8A	ENST00000310298.8	TSL:1	c.1007C>G	p.Ser336Cys	missense	Exon 12 of 23	ENSP00000311453.4	O60658-1
PDE8A	ENST00000339708.9	TSL:1	c.869C>G	p.Ser290Cys	missense	Exon 10 of 21	ENSP00000340679.5	O60658-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461538

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111694

Other (OTH)

AF:

0.00

AC:

AN:

60388

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.13

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.63

M_CAP

Benign

0.0092

MetaRNN

Benign

0.098

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

PhyloP100

0.79

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.2

REVEL

Benign

0.18

Sift

Benign

0.19

Sift4G

Benign

0.087

Polyphen

0.0

Vest4

0.19

MutPred

0.50

Loss of disorder (P = 0.0087)

MVP

0.12

MPC

0.18

ClinPred

0.058

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.063

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over