Genetic Variant PDE4C:p.Pro164Leu (chr19-18220882-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001098818.4(PDE4C):c.491C>T(p.Pro164Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000932 in 1,608,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

PDE4C
NM_001098818.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.05

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08331469).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE4C	NM_001098818.4 link	c.491C>T	p.Pro164Leu	missense_variant	Exon 5 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.491C>T	p.Pro164Leu	missense_variant	Exon 5 of 15	1	NM_001098818.4	ENSP00000262805.10		Q08493-3
PDE4C	ENST00000355502.7 link	c.587C>T	p.Pro196Leu	missense_variant	Exon 9 of 19	2		ENSP00000347689.2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000878

AC:

AN:

239212

AF XY:

0.0000853

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000300

Gnomad ASJ exome

AF:

0.000104

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000175

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000975

AC:

142

AN:

1456452

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

723774

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33460

American (AMR)

AF:

0.0000686

AC:

AN:

43758

Ashkenazi Jewish (ASJ)

AF:

0.000155

AC:

AN:

25814

East Asian (EAS)

AF:

0.00

AC:

AN:

39532

South Asian (SAS)

AF:

0.00

AC:

AN:

84450

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53052

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000118

AC:

131

AN:

1110422

Other (OTH)

AF:

0.0000332

AC:

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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

AF:

0.0000525

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41578

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000947

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 27, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.587C>T (p.P196L) alteration is located in exon 6 (coding exon 5) of the PDE4C gene. This alteration results from a C to T substitution at nucleotide position 587, causing the proline (P) at amino acid position 196 to be replaced by a leucine (L). 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

0.063

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.048

.;T;.;.;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.35

T;.;T;T;.

M_CAP

Benign

0.055

MetaRNN

Benign

0.083

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

.;M;.;.;M

PhyloP100

1.0

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.2

N;.;N;N;.

REVEL

Benign

0.086

Sift

Benign

0.66

T;.;T;T;.

Sift4G

Benign

0.11

T;T;T;T;T

Polyphen

0.020, 0.0

.;B;.;B;B

Vest4

0.42

MVP

0.75

MPC

0.40

ClinPred

0.047

GERP RS

2.4

PromoterAI

0.057

Neutral

(source)

Varity_R

0.056

gMVP

0.36

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over