Genetic Variant PDE4C:p.Ile569Thr (chr19-18211266-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001098818.4(PDE4C):c.1706T>C(p.Ile569Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000035 in 1,430,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I569V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

PDE4C
NM_001098818.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.92

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:

ENSG00000285188 (HGNC:):

ENSG00000285188 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE4C	NM_001098818.4 link	c.1706T>C	p.Ile569Thr	missense_variant	Exon 15 of 15	ENST00000262805.17	NP_001092288.1	Q08493-3Q32MM7P78505

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE4C	ENST00000262805.17 link	c.1706T>C	p.Ile569Thr	missense_variant	Exon 15 of 15	1	NM_001098818.4	ENSP00000262805.10		Q08493-3
ENSG00000285188	ENST00000355502.7 link	c.1802T>C	p.Ile601Thr	missense_variant	Exon 19 of 19	2		ENSP00000347689.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000440

AC:

AN:

227340

Hom.:

AF XY:

0.00000819

AC XY:

AN XY:

122136

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000350

AC:

AN:

1430546

Hom.:

Cov.:

AF XY:

0.00000283

AC XY:

AN XY:

706966

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000366

Gnomad4 OTH exome

AF:

0.00

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

Mar 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1802T>C (p.I601T) alteration is located in exon 16 (coding exon 15) of the PDE4C gene. This alteration results from a T to C substitution at nucleotide position 1802, causing the isoleucine (I) at amino acid position 601 to be replaced by a threonine (T). 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

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

.;D;.;.;D;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;.;D;D;.;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Uncertain

0.39

MutationAssessor

Pathogenic

3.6

.;H;.;.;H;.

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-4.8

D;.;D;D;.;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;.;D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

.;D;.;D;D;.

Vest4

0.85

MutPred

0.90

Loss of stability (P = 0.0444);Loss of stability (P = 0.0444);.;.;Loss of stability (P = 0.0444);.;

MVP

0.97

MPC

1.3

ClinPred

1.0

GERP RS

3.9

Varity_R

0.88

gMVP

0.77

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