11-72584916-C-T

Position:

• chr11-72584916-C-T

Variant summary

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

The NM_002599.5(PDE2A):​c.1315G>A​(p.Glu439Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDE2A NM_002599.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58

Genes affected

PDE2A (HGNC:8777): (phosphodiesterase 2A) Enables several functions, including 3',5'-cyclic-nucleotide phosphodiesterase activity; anion binding activity; and metal ion binding activity. Involved in several processes, including cellular response to organic cyclic compound; cyclic-nucleotide-mediated signaling; and regulation of vascular permeability. Located in several cellular components, including cytosol; mitochondrial membrane; and perinuclear region of cytoplasm. Colocalizes with plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

PDE2A-AS2 (HGNC:40434): (PDE2A antisense RNA 2)

ACMG classification

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/exons	MANE	Protein	UniProt
PDE2A	NM_002599.5	c.1315G>A	p.Glu439Lys	missense_variant	17/31	ENST00000334456.10	NP_002590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE2A	ENST00000334456.10	c.1315G>A	p.Glu439Lys	missense_variant	17/31	1	NM_002599.5	ENSP00000334910.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2023

The c.1315G>A (p.E439K) alteration is located in exon 17 (coding exon 17) of the PDE2A gene. This alteration results from a G to A substitution at nucleotide position 1315, causing the glutamic acid (E) at amino acid position 439 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	0.97
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;.;.;.;T;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.5	D;D;.;D;N;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.024	D;D;.;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D;.
Polyphen		0.71	P;.;.;.;P;.;.
Vest4		0.69
MutPred		0.50		Loss of sheet (P = 0.0315);.;.;.;.;.;.;
MVP		0.91
MPC		2.4
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.44
gMVP		0.92

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

Other links and lift over

dbSNP: rs1855895158; hg19: chr11-72295960; COSMIC: COSV57809356; COSMIC: COSV57809356;