Genetic Variant PDE4C:p.Asn410Lys (chr19-18218153-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001098818.4(PDE4C):c.1230C>G(p.Asn410Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000434 in 1,612,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

PDE4C
NM_001098818.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.05

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE4C	NM_001098818.4 link	c.1230C>G	p.Asn410Lys	missense_variant	Exon 11 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.1230C>G	p.Asn410Lys	missense_variant	Exon 11 of 15	1	NM_001098818.4	ENSP00000262805.10		Q08493-3
ENSG00000285188	ENST00000355502.7 link	c.1326C>G	p.Asn442Lys	missense_variant	Exon 15 of 19	2		ENSP00000347689.2

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251130

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135710

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.0000199

AC:

AN:

1460278

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726412

show subpopulations

Gnomad4 AFR exome

AF:

0.000718

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000269

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.000385

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1326C>G (p.N442K) alteration is located in exon 12 (coding exon 11) of the PDE4C gene. This alteration results from a C to G substitution at nucleotide position 1326, causing the asparagine (N) at amino acid position 442 to be replaced by a lysine (K). 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

0.82

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

.;T;.;.;T;D

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;.;D;D;.;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.71

D;D;D;D;D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

1.7

.;L;.;.;L;.

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.4

D;.;D;D;.;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

D;.;D;D;.;D

Sift4G

Uncertain

0.047

D;D;T;D;D;T

Polyphen

1.0, 0.66

.;D;.;P;D;.

Vest4

0.78

MutPred

0.65

Gain of ubiquitination at N442 (P = 0.0325);Gain of ubiquitination at N442 (P = 0.0325);.;.;Gain of ubiquitination at N442 (P = 0.0325);.;

MVP

0.93

MPC

1.2

ClinPred

0.62

GERP RS

4.8

Varity_R

0.78

gMVP

0.44

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