chr2-178104442-GTC-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PVS1_StrongBS1_SupportingBS2

The ENST00000358450.8(PDE11A):c.20_21delGA(p.Arg7ThrfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,614,002 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 8 hom. )

Consequence

PDE11A
ENST00000358450.8 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:1

Conservation

PhyloP100: 1.86

Publications

11 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 links:

CYCTP (HGNC:24424): (cytochrome c, testis, pseudogene) Predicted to enable heme binding activity. Predicted to act upstream of or within hydrogen peroxide metabolic process and positive regulation of intrinsic apoptotic signaling pathway. [provided by Alliance of Genome Resources, Apr 2022]

CYCTP links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00258 (392/152228) while in subpopulation NFE AF = 0.00288 (196/68018). AF 95% confidence interval is 0.00255. There are 0 homozygotes in GnomAd4. There are 217 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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 392 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE11A	NM_001077197.2 link	c.20_21delGA	p.Arg7ThrfsTer30	frameshift_variant	Exon 2 of 21		NP_001070665.1	Q9HCR9-2
CYCTP		n.178104444_178104445delCT		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000358450.8 link	c.20_21delGA	p.Arg7ThrfsTer30	frameshift_variant	Exon 2 of 21	1		ENSP00000351232.4		Q9HCR9-2
CYCTP	ENST00000504253.1 link	n.27_28delGA		non_coding_transcript_exon_variant	Exon 1 of 3	6

Frequencies

GnomAD3 genomes

AF:

0.00258

AC:

392

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00269

Gnomad SAS

AF:

0.00208

Gnomad FIN

AF:

0.0123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00288

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00305

AC:

760

AN:

249534

AF XY:

0.00299

show subpopulations

Gnomad AFR exome

AF:

0.000387

Gnomad AMR exome

AF:

0.000869

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00300

Gnomad FIN exome

AF:

0.0129

Gnomad NFE exome

AF:

0.00283

Gnomad OTH exome

AF:

0.00363

GnomAD4 exome

AF:

0.00291

AC:

4258

AN:

1461774

Hom.:

AF XY:

0.00286

AC XY:

2078

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33480

American (AMR)

AF:

0.000850

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00153

AC:

AN:

26132

East Asian (EAS)

AF:

0.00189

AC:

AN:

39680

South Asian (SAS)

AF:

0.00108

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0137

AC:

733

AN:

53414

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00279

AC:

3106

AN:

1111938

Other (OTH)

AF:

0.00252

AC:

152

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

205

411

616

822

1027

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

232

348

464

580

<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:

0.00258

AC:

392

AN:

152228

Hom.:

Cov.:

AF XY:

0.00292

AC XY:

217

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000554

AC:

AN:

41540

American (AMR)

AF:

0.000458

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00270

AC:

AN:

5188

South Asian (SAS)

AF:

0.00208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0123

AC:

130

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00288

AC:

196

AN:

68018

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

101

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:

0.000678

Hom.:

Bravo

AF:

0.00162

EpiCase

AF:

0.00267

EpiControl

AF:

0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pigmented nodular adrenocortical disease, primary, 2

Pathogenic:1Uncertain:2

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

NM_001077197.1:c.20_21delGA in PDE11A gene has an allele frequency of 0.013 in European (Finnish) subpopulation in the gnomAD database. This variant is expected to result in an absent or disrupted protein product. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in PDE11A cause disease. The available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ACMG/AMP criteria applied: BS1. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

Jul 26, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PDE11A: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.9

Mutation Taster

=156/44

disease causing (ClinVar)

(source)

Splicing

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