Genetic Variant NM_002605.3:c.1097C>T (chr15-85109113-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002605.3(PDE8A):c.1097C>T(p.Ala366Val) 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 1,457,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PDE8A
NM_002605.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.30

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.120289415).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE8A	NM_002605.3 link	c.1097C>T	p.Ala366Val	missense_variant	Exon 12 of 22	ENST00000394553.6	NP_002596.1	O60658-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE8A	ENST00000394553.6 link	c.1097C>T	p.Ala366Val	missense_variant	Exon 12 of 22	1	NM_002605.3	ENSP00000378056.1		O60658-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250612

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135432

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457734

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725386

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1097C>T (p.A366V) alteration is located in exon 12 (coding exon 12) of the PDE8A gene. This alteration results from a C to T substitution at nucleotide position 1097, causing the alanine (A) at amino acid position 366 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.17

T;.;T;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.67

T;T;.;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.7

L;.;L;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.021

D;D;D;D

Sift4G

Uncertain

0.027

D;D;D;D

Polyphen

0.062

B;.;B;B

Vest4

0.18

MutPred

0.28

Gain of methylation at K363 (P = 0.0659);.;Gain of methylation at K363 (P = 0.0659);.;

MVP

0.35

MPC

0.18

ClinPred

0.12

GERP RS

0.98

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.050

gMVP

0.25

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over