Genetic Variant PDE4C:p.Gly547Asp (chr19-18211814-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001098818.4(PDE4C):c.1640G>A(p.Gly547Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G547V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PDE4C
NM_001098818.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.53

Publications

0 publications found

Variant links:

Genes affected

PDE4C (HGNC:8782): (phosphodiesterase 4C) The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE4 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 described for this gene.[provided by RefSeq, Jul 2011]

PDE4C links:

PDE4C (HGNC:):

PDE4C links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.866

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098818.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDE4C	NM_001098818.4	MANE Select	c.1640G>A	p.Gly547Asp	missense	Exon 14 of 15	NP_001092288.1	Q08493-3
PDE4C	NM_000923.6		c.1736G>A	p.Gly579Asp	missense	Exon 15 of 16	NP_000914.2	Q08493-1
PDE4C	NM_001330172.2		c.1736G>A	p.Gly579Asp	missense	Exon 15 of 16	NP_001317101.1	Q08493-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDE4C	ENST00000262805.17	TSL:1 MANE Select	c.1640G>A	p.Gly547Asp	missense	Exon 14 of 15	ENSP00000262805.10	Q08493-3
PDE4C	ENST00000355502.7	TSL:2	c.1736G>A	p.Gly579Asp	missense	Exon 18 of 19	ENSP00000347689.2
PDE4C	ENST00000594465.7	TSL:1	c.1736G>A	p.Gly579Asp	missense	Exon 14 of 15	ENSP00000470210.1	Q08493-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

0.24

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.87

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.9

PhyloP100

7.5

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.3

REVEL

Uncertain

0.63

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.75

MutPred

0.70

Gain of solvent accessibility (P = 0.0638)

MVP

0.94

MPC

1.4

ClinPred

1.0

GERP RS

3.8

Varity_R

0.79

gMVP

0.69

Mutation Taster

=58/42

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