chr2-177871338-G-A

Variant names:

• chr2-177871338-G-A
• rs2037757
• NM_016953.4:c.1367+4521C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016953.4(PDE11A):​c.1367+4521C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 151,596 control chromosomes in the GnomAD database, including 10,172 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (10172 hom., cov: 30)
• Consequence: PDE11A NM_016953.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.205
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE11A	NM_016953.4	c.1367+4521C>T		intron_variant	Intron 5 of 19	ENST00000286063.11	NP_058649.3
PDE11A	NM_001077197.2	c.617+4521C>T		intron_variant	Intron 6 of 20		NP_001070665.1
PDE11A	NM_001077358.2	c.293+4521C>T		intron_variant	Intron 4 of 18		NP_001070826.1
PDE11A	NM_001077196.2	c.35+4521C>T		intron_variant	Intron 2 of 16		NP_001070664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11	c.1367+4521C>T		intron_variant	Intron 5 of 19	1	NM_016953.4	ENSP00000286063.5

Frequencies

GnomAD3 genomes AF: 0.335 AC: 50690 AN: 151482 Hom.: 10161 Cov.: 30

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.328

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.334 AC: 50706 AN: 151596 Hom.: 10172 Cov.: 30 AF XY: 0.341 AC XY: 25235 AN XY: 74028

African (AFR) AF: 0.124 AC: 5150 AN: 41410

American (AMR) AF: 0.502 AC: 7648 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 1398 AN: 3468

East Asian (EAS) AF: 0.530 AC: 2712 AN: 5118

South Asian (SAS) AF: 0.334 AC: 1601 AN: 4800

European-Finnish (FIN) AF: 0.474 AC: 4926 AN: 10394

Middle Eastern (MID) AF: 0.281 AC: 82 AN: 292

European-Non Finnish (NFE) AF: 0.387 AC: 26286 AN: 67872

Other (OTH) AF: 0.331 AC: 695 AN: 2102

Alfa AF: 0.369 Hom.: 5658

Bravo AF: 0.332

Asia WGS AF: 0.468 AC: 1627 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.8
DANN	Benign	0.51
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2037757; hg19: chr2-178736065;