19-18216838-G-A

Variant names:

• chr19-18216838-G-A
• NM_001098818.4:c.1292C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001098818.4(PDE4C):​c.1292C>T​(p.Ala431Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PDE4C NM_001098818.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.43

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]

ENSG00000285188 (HGNC:):

ACMG classification

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, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE4C	NM_001098818.4	c.1292C>T	p.Ala431Val	missense_variant	Exon 12 of 15	ENST00000262805.17	NP_001092288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE4C	ENST00000262805.17	c.1292C>T	p.Ala431Val	missense_variant	Exon 12 of 15	1	NM_001098818.4	ENSP00000262805.10
ENSG00000285188	ENST00000355502.7	c.1388C>T	p.Ala463Val	missense_variant	Exon 16 of 19	2		ENSP00000347689.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1388C>T (p.A463V) alteration is located in exon 13 (coding exon 12) of the PDE4C gene. This alteration results from a C to T substitution at nucleotide position 1388, causing the alanine (A) at amino acid position 463 to be replaced by a valine (V). 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	0.73
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	.;D;.;.;D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;.;D;D;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.5	.;M;.;.;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D;.;D;D;.;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;.;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;D;D;.
Vest4		0.95
MutPred		0.82		Gain of ubiquitination at K467 (P = 0.0828);Gain of ubiquitination at K467 (P = 0.0828);.;.;Gain of ubiquitination at K467 (P = 0.0828);.;
MVP		0.96
MPC		1.1
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.77
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-18327648;