chr2-178072266-TA-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1BP6BS1BS2

The NM_016953.4(PDE11A):c.171delT(p.Thr58ProfsTer41) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,613,682 control chromosomes in the GnomAD database, including 122 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0018 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 115 hom. )

Consequence

PDE11A
NM_016953.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 0.635

Publications

13 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: Likely_benign. The variant received -1 ACMG points.

PVS1

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

BP6

Variant 2-178072266-TA-T is Benign according to our data. Variant chr2-178072266-TA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 208602.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00183 (279/152252) while in subpopulation SAS AF = 0.041 (197/4808). AF 95% confidence interval is 0.0363. There are 7 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 279 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016953.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE11A	NM_016953.4	MANE Select	c.171delT	p.Thr58ProfsTer41	frameshift	Exon 1 of 20	NP_058649.3
	PDE11A	NM_001077197.2		c.162+32035delT		intron	N/A	NP_001070665.1	Q9HCR9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE11A	ENST00000286063.11	TSL:1 MANE Select	c.171delT	p.Thr58ProfsTer41	frameshift	Exon 1 of 20	ENSP00000286063.5	Q9HCR9-1
	PDE11A	ENST00000358450.8	TSL:1	c.162+32035delT		intron	N/A	ENSP00000351232.4	Q9HCR9-2

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

278

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0407

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000471

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00563

AC:

1403

AN:

249420

AF XY:

0.00778

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00885

Gnomad EAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.000924

Gnomad OTH exome

AF:

0.00460

GnomAD4 exome

AF:

0.00313

AC:

4575

AN:

1461430

Hom.:

115

Cov.:

AF XY:

0.00441

AC XY:

3207

AN XY:

726970

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33466

American (AMR)

AF:

0.000403

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00926

AC:

242

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39688

South Asian (SAS)

AF:

0.0394

AC:

3393

AN:

86204

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.0196

AC:

113

AN:

5768

European-Non Finnish (NFE)

AF:

0.000498

AC:

554

AN:

1111748

Other (OTH)

AF:

0.00406

AC:

245

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

368

737

1105

1474

1842

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.00183

AC:

279

AN:

152252

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

185

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41564

American (AMR)

AF:

0.000915

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.0410

AC:

197

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000471

AC:

AN:

68000

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00101

Hom.:

Bravo

AF:

0.000937

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Pigmented nodular adrenocortical disease, primary, 2 (2)

Bardet-Biedl syndrome 16 (1)

not specified (1)

PDE11A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.64

Mutation Taster

=43/157

disease causing (fs/PTC)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over