2-177663890-A-C

Position:

• chr2-177663890-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016953.4(PDE11A):​c.2622T>G​(p.Asp874Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PDE11A NM_016953.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.182

Genes affected

PDE11A (HGNC:8773): (phosphodiesterase 11A) The 3',5'-cyclic nucleotides cAMP and cGMP function as second messengers in a wide variety of signal transduction pathways. 3',5'-cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP to the corresponding 5'-monophosphates and provide a mechanism to downregulate cAMP and cGMP signaling. This gene encodes a member of the PDE protein superfamily. Mutations in this gene are a cause of Cushing disease and adrenocortical hyperplasia. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PDE11A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE11A	NM_016953.4	c.2622T>G	p.Asp874Glu	missense_variant	19/20	ENST00000286063.11	NP_058649.3
PDE11A	NM_001077197.2	c.1872T>G	p.Asp624Glu	missense_variant	20/21		NP_001070665.1
PDE11A	NM_001077358.2	c.1548T>G	p.Asp516Glu	missense_variant	18/19		NP_001070826.1
PDE11A	NM_001077196.2	c.1290T>G	p.Asp430Glu	missense_variant	16/17		NP_001070664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11	c.2622T>G	p.Asp874Glu	missense_variant	19/20	1	NM_016953.4	ENSP00000286063.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453790 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 723964

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2024

The c.2622T>G (p.D874E) alteration is located in exon 19 (coding exon 19) of the PDE11A gene. This alteration results from a T to G substitution at nucleotide position 2622, causing the aspartic acid (D) at amino acid position 874 to be replaced by a glutamic acid (E). 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	0.76
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	6.6
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;.;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.81
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	D;D;T;D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.0	M;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Uncertain	0.57
Sift	Benign	0.055	T;T;D;D
Sift4G	Uncertain	0.057	T;T;T;T
Polyphen		0.71	P;.;.;D
Vest4		0.90
MutPred		0.77		Gain of MoRF binding (P = 0.4231);.;.;.;
MVP		0.62
MPC		0.61
ClinPred		0.99	D
GERP RS		-7.1
Varity_R		0.61
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-178528618;