2-178014454-G-A

Position:

chr2-178014454-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2

The ENST00000286063.11(PDE11A):c.919C>T(p.Arg307Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,611,942 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0029 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0044 ( 16 hom. )

Consequence

PDE11A
ENST00000286063.11 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2B:3

Conservation

PhyloP100: 3.49

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BS2

High AC in GnomAd4 at 441 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE11A	NM_016953.4 linkuse as main transcript	c.919C>T	p.Arg307Ter	stop_gained	2/20	ENST00000286063.11	NP_058649.3
PDE11A	NM_001077197.2 linkuse as main transcript	c.169C>T	p.Arg57Ter	stop_gained	3/21		NP_001070665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11 linkuse as main transcript	c.919C>T	p.Arg307Ter	stop_gained	2/20	1	NM_016953.4	ENSP00000286063	P1	Q9HCR9-1
PDE11A	ENST00000358450.8 linkuse as main transcript	c.169C>T	p.Arg57Ter	stop_gained	3/21	1		ENSP00000351232		Q9HCR9-2

Frequencies

GnomAD3 genomes

AF:

0.00289

AC:

440

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000990

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00274

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00481

Gnomad OTH

AF:

0.00384

GnomAD3 exomes

AF:

0.00288

AC:

721

AN:

250432

Hom.:

AF XY:

0.00286

AC XY:

387

AN XY:

135368

show subpopulations

Gnomad AFR exome

AF:

0.000985

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00239

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00134

Gnomad FIN exome

AF:

0.00269

Gnomad NFE exome

AF:

0.00464

Gnomad OTH exome

AF:

0.00279

GnomAD4 exome

AF:

0.00440

AC:

6426

AN:

1459698

Hom.:

Cov.:

AF XY:

0.00428

AC XY:

3112

AN XY:

726300

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.00222

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00125

Gnomad4 FIN exome

AF:

0.00328

Gnomad4 NFE exome

AF:

0.00517

Gnomad4 OTH exome

AF:

0.00418

GnomAD4 genome

AF:

0.00290

AC:

441

AN:

152244

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

202

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00274

Gnomad4 NFE

AF:

0.00481

Gnomad4 OTH

AF:

0.00380

Alfa

AF:

0.00422

Hom.:

Bravo

AF:

0.00275

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00296

AC:

359

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00540

EpiControl

AF:

0.00516

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2019	This variant is associated with the following publications: (PMID: 18559625, 20351491, 25525159, 23771924, 26820475, 21047926, 16767104, 29495593, 30262796, 32098292) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PDE11A p.Arg57X variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs76308115), Cosmic (FATHMM prediction score of neutral) and ClinVar (classified as likely benign by GeneDx and pathogenic by Genomic Research Center, Shahid Beheshti University of Medical Sciences for pigmented nodular adrenocortical disease, 2). The variant was identified in control databases in 849 of 281828 chromosomes (5 homozygous) at a frequency of 0.003012 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 613 of 128514 chromosomes (freq: 0.00477), Other in 26 of 7184 chromosomes (freq: 0.003619), European (Finnish) in 73 of 25042 chromosomes (freq: 0.002915), Ashkenazi Jewish in 25 of 10350 chromosomes (freq: 0.002415), South Asian in 41 of 30580 chromosomes (freq: 0.001341), Latino in 43 of 35376 chromosomes (freq: 0.001216) and African in 28 of 24956 chromosomes (freq: 0.001122); it was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg57X variant leads to a premature stop codon at position 57 which is predicted to lead to a truncated or absent protein and loss of function. Other loss of function variants (c.919C>T, p.R317X) have been identified in the PDE11A gene as causal for Cushing Syndrome and ovarian cysts (Hovarth_2006_PMID: 16767104), indicating that stop gain variants in the PDE11A gene are disease-causing. Further, MutationTaster predicts the variant to be disease causing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PDE11A: BS1, BS2 -

Pigmented nodular adrenocortical disease, primary, 2

Pathogenic:2

Pathogenic, flagged submission	literature only	OMIM	Jul 01, 2006	- -
Pathogenic, flagged submission	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Nov 02, 2020

ACMG classification criteria: PVS1, BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

0.19

Eigen_PC

Benign

0.014

FATHMM_MKL

Uncertain

0.91

MutationTaster

Benign

1.0

A;A

Vest4

0.86

GERP RS

0.033

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over