19-18211054-C-T

Variant summary

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

The NM_001098818.4(PDE4C):​c.1918G>A​(p.Glu640Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,614,120 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: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

PDE4C
NM_001098818.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.84
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]

Genome browser will be placed here

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=0.11003274).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PDE4CNM_001098818.4 linkc.1918G>A p.Glu640Lys 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
PDE4CENST00000262805.17 linkc.1918G>A p.Glu640Lys missense_variant Exon 15 of 15 1 NM_001098818.4 ENSP00000262805.10 Q08493-3
ENSG00000285188ENST00000355502.7 linkc.2014G>A p.Glu672Lys missense_variant Exon 19 of 19 2 ENSP00000347689.2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152236
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
250968
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135672
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000376
AC:
55
AN:
1461884
Hom.:
0
Cov.:
31
AF XY:
0.0000344
AC XY:
25
AN XY:
727242
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000477
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152236
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 13, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2014G>A (p.E672K) alteration is located in exon 16 (coding exon 15) of the PDE4C gene. This alteration results from a G to A substitution at nucleotide position 2014, causing the glutamic acid (E) at amino acid position 672 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
Benign
0.076
BayesDel_addAF
Benign
-0.085
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
13
DANN
Benign
0.13
DEOGEN2
Benign
0.045
.;T;.;.;T;T
Eigen
Benign
-0.71
Eigen_PC
Benign
-0.65
FATHMM_MKL
Benign
0.54
D
LIST_S2
Benign
0.63
T;.;T;T;.;T
M_CAP
Benign
0.075
D
MetaRNN
Benign
0.11
T;T;T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.2
.;L;.;.;L;.
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-0.32
N;.;N;N;.;N
REVEL
Benign
0.081
Sift
Benign
1.0
T;.;T;T;.;T
Sift4G
Benign
0.30
T;T;T;T;T;T
Polyphen
0.16, 0.39
.;B;.;B;B;.
Vest4
0.24
MVP
0.79
MPC
0.47
ClinPred
0.15
T
GERP RS
3.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.12
gMVP
0.55

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.

Other links and lift over

dbSNP: rs535422150; hg19: chr19-18321864; API