2-177669524-C-G

Variant names:

• chr2-177669524-C-G
• rs911385258
• NM_016953.4:c.2531G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_016953.4(PDE11A):​c.2531G>C​(p.Arg844Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000842 in 1,306,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: PDE11A NM_016953.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04

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-AS1 (HGNC:40433): (PDE11A antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE11A	NM_016953.4	c.2531G>C	p.Arg844Pro	missense_variant	Exon 18 of 20	ENST00000286063.11	NP_058649.3
PDE11A	NM_001077197.2	c.1781G>C	p.Arg594Pro	missense_variant	Exon 19 of 21		NP_001070665.1
PDE11A	NM_001077358.2	c.1457G>C	p.Arg486Pro	missense_variant	Exon 17 of 19		NP_001070826.1
PDE11A	NM_001077196.2	c.1199G>C	p.Arg400Pro	missense_variant	Exon 15 of 17		NP_001070664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11	c.2531G>C	p.Arg844Pro	missense_variant	Exon 18 of 20	1	NM_016953.4	ENSP00000286063.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000842 AC: 11 AN: 1306694 Hom.: 0 Cov.: 20 AF XY: 0.00000759 AC XY: 5 AN XY: 658868

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: 0.0000103

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2531G>C (p.R844P) alteration is located in exon 18 (coding exon 18) of the PDE11A gene. This alteration results from a G to C substitution at nucleotide position 2531, causing the arginine (R) at amino acid position 844 to be replaced by a proline (P). 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	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.7	M;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Pathogenic	0.74
Sift	Benign	0.13	T;T;T;T
Sift4G	Uncertain	0.046	D;T;T;T
Polyphen		1.0	D;.;.;D
Vest4		0.93
MutPred		0.57		Loss of helix (P = 0.079);.;.;.;
MVP		0.93
MPC		0.77
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs911385258; hg19: chr2-178534252;