chr11-72577414-G-C

Position:

• chr11-72577414-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_002599.5(PDE2A):​c.2796C>G​(p.Ile932Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDE2A NM_002599.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.906

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PDE2A. . Gene score misZ 4.056 (greater than the threshold 3.09). Trascript score misZ 3.8645 (greater than threshold 3.09). GenCC has associacion of gene with intellectual developmental disorder with paroxysmal dyskinesia or seizures, infantile convulsions and choreoathetosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09551117).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE2A	NM_002599.5	c.2796C>G	p.Ile932Met	missense_variant	31/31	ENST00000334456.10	NP_002590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE2A	ENST00000334456.10	c.2796C>G	p.Ile932Met	missense_variant	31/31	1	NM_002599.5	ENSP00000334910.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Aug 28, 2024

The c.2796C>G (p.I932M) alteration is located in exon 31 (coding exon 31) of the PDE2A gene. This alteration results from a C to G substitution at nucleotide position 2796, causing the isoleucine (I) at amino acid position 932 to be replaced by a methionine (M). 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	0.067
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.079	T;.;.;.;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.83	T;T;T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.096	T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N;.;.;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.32	N;N;.;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.17	T;T;.;T;T;T
Sift4G	Benign	0.66	T;T;T;T;T;T
Polyphen		0.0010	B;.;.;.;B;.
Vest4		0.073
MutPred		0.36		Gain of disorder (P = 0.0132);.;.;.;.;.;
MVP		0.29
MPC		1.3
ClinPred		0.12	T
GERP RS		3.2
Varity_R		0.058
gMVP		0.12

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: rs1216399127; hg19: chr11-72288458;