rs202117698

chr2-178104442-GTC-Gchr2-178104442-GTC-GTCTC

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_Strong BS2

The ENST00000358450.8(PDE11A):c.20_21del(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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 1.86

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 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 6 pathogenic variants in the truncated region.
• BS2: High AC in GnomAd at 392 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE11A	NM_001077197.2	c.20_21del	p.Arg7ThrfsTer30	frameshift_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE11A	ENST00000358450.8	c.20_21del	p.Arg7ThrfsTer30	frameshift_variant	2/21	1
CYCTP	ENST00000504253.1	n.27_28del		non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 392 AN: 152110 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00305 AC: 760 AN: 249534 Hom.: 1 AF XY: 0.00299 AC XY: 405 AN XY: 135372

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 SAS exome AF: 0.00108

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.: 8 AF XY: 0.00286 AC XY: 2078 AN XY: 727188

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00189

Gnomad4 SAS exome AF: 0.00108

Gnomad4 FIN exome AF: 0.0137

Gnomad4 NFE exome AF: 0.00279

Gnomad4 OTH exome AF: 0.00252

GnomAD4 genome AF: 0.00258 AC: 392 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00292 AC XY: 217 AN XY: 74422

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.0123

Gnomad4 NFE AF: 0.00288

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000678 Hom.: 0

Bravo AF: 0.00162

EpiCase AF: 0.00267

EpiControl AF: 0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

PDE11A: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs202117698; hg19: chr2-178969169;