rs188985665

Positions:

• chr2-178014388-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PVS1 PP5_Strong BS2

The ENST00000286063.11(PDE11A):​c.985C>T​(p.Arg329Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,611,182 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00043 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: PDE11A ENST00000286063.11 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 1.79

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-178014388-G-A is Pathogenic according to our data. Variant chr2-178014388-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 225434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}. Variant chr2-178014388-G-A is described in Lovd as [Likely_pathogenic].
• BS2: High AC in GnomAd4 at 65 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE11A	NM_016953.4	c.985C>T	p.Arg329Ter	stop_gained	2/20	ENST00000286063.11	NP_058649.3
PDE11A	NM_001077197.2	c.235C>T	p.Arg79Ter	stop_gained	3/21		NP_001070665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11	c.985C>T	p.Arg329Ter	stop_gained	2/20	1	NM_016953.4	ENSP00000286063	P1
PDE11A	ENST00000358450.8	c.235C>T	p.Arg79Ter	stop_gained	3/21	1		ENSP00000351232

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152118 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000267 AC: 67 AN: 251004 Hom.: 0 AF XY: 0.000273 AC XY: 37 AN XY: 135650

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000764

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000217 AC: 317 AN: 1458946 Hom.: 1 Cov.: 29 AF XY: 0.000264 AC XY: 192 AN XY: 726002

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000530

Gnomad4 SAS exome AF: 0.000754

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152236 Hom.: 1 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74424

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000241 Hom.: 0

Bravo AF: 0.000540

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pigmented nodular adrenocortical disease, primary, 2 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 28, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely pathogenic, flagged submission	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 12, 2022

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Has not been previously published in an individual with PDE11A-related disease as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 34426522, 31589614, 31921681, 30262796) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	A;A
Vest4		0.95
GERP RS		2.3

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: rs188985665; hg19: chr2-178879115; COSMIC: COSV104587953; COSMIC: COSV104587953;