2-177728150-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 16P and 2B. PVS1PP5_Very_StrongBS1_SupportingBS2_Supporting

The NM_016953.4(PDE11A):c.1811C>G(p.Ser604*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

PDE11A
NM_016953.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.41

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

pigmented nodular adrenocortical disease, primary, 2
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine
primary pigmented nodular adrenocortical disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PDE11A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PVS1

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

PP5

Variant 2-177728150-G-C is Pathogenic according to our data. Variant chr2-177728150-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 225433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000076 (111/1461152) while in subpopulation EAS AF = 0.00277 (110/39674). AF 95% confidence interval is 0.00235. There are 0 homozygotes in GnomAdExome4. There are 56 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PDE11A	NM_016953.4 link	c.1811C>G	p.Ser604*	stop_gained	Exon 11 of 20	ENST00000286063.11	NP_058649.3
PDE11A	NM_001077197.2 link	c.1061C>G	p.Ser354*	stop_gained	Exon 12 of 21		NP_001070665.1
PDE11A	NM_001077358.2 link	c.737C>G	p.Ser246*	stop_gained	Exon 10 of 19		NP_001070826.1
PDE11A	NM_001077196.2 link	c.479C>G	p.Ser160*	stop_gained	Exon 8 of 17		NP_001070664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11 link	c.1811C>G	p.Ser604*	stop_gained	Exon 11 of 20	1	NM_016953.4	ENSP00000286063.5

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000108

AC:

AN:

249272

AF XY:

0.0000890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000760

AC:

111

AN:

1461152

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

726914

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.00

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00277

AC:

110

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111506

Other (OTH)

AF:

0.0000166

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41524

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.000115

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pigmented nodular adrenocortical disease, primary, 2

Pathogenic:2

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:reference population

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;.;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.0

.;.;.;.

MetaRNN

Benign

0.0

.;.;.;.

MutationAssessor

Benign

0.0

.;.;.;.

PhyloP100

7.4

PROVEAN

Benign

0.0

.;.;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.;.

Sift4G

Pathogenic

0.0

.;.;.;.

Vest4

0.95

ClinPred

0.68

GERP RS

5.5

Mutation Taster

=26/174

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over