rs1405647

Variant names:

• chr2-177894135-A-C
• rs1405647
• NM_016953.4:c.1302+3923T>G

Variant summary

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

The NM_016953.4(PDE11A):​c.1302+3923T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 151,894 control chromosomes in the GnomAD database, including 17,122 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 0.45 (17122 hom., cov: 31)
• Consequence: PDE11A NM_016953.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE11A	NM_016953.4	c.1302+3923T>G		intron_variant	Intron 4 of 19	ENST00000286063.11	NP_058649.3
PDE11A	NM_001077197.2	c.552+3923T>G		intron_variant	Intron 5 of 20		NP_001070665.1
PDE11A	NM_001077358.2	c.228+3923T>G		intron_variant	Intron 3 of 18		NP_001070826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11	c.1302+3923T>G		intron_variant	Intron 4 of 19	1	NM_016953.4	ENSP00000286063.5

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68213 AN: 151776 Hom.: 17085 Cov.: 31

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.429

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

GnomAD4 genome AF: 0.450 AC: 68304 AN: 151894 Hom.: 17122 Cov.: 31 AF XY: 0.443 AC XY: 32912 AN XY: 74220

African (AFR) AF: 0.674 AC: 27896 AN: 41382

American (AMR) AF: 0.301 AC: 4587 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1094 AN: 3468

East Asian (EAS) AF: 0.263 AC: 1358 AN: 5164

South Asian (SAS) AF: 0.443 AC: 2133 AN: 4814

European-Finnish (FIN) AF: 0.367 AC: 3880 AN: 10566

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 26028 AN: 67938

Other (OTH) AF: 0.426 AC: 898 AN: 2106

Alfa AF: 0.459 Hom.: 3079

Bravo AF: 0.451

Asia WGS AF: 0.357 AC: 1243 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.92
DANN	Benign	0.43
PhyloP100		-1.3
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: rs1405647; hg19: chr2-178758862;