2-177819993-G-C

Variant names:

• chr2-177819993-G-C
• rs7567851
• NM_016953.4:c.1576+227C>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.1576+227C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 150,514 control chromosomes in the GnomAD database, including 1,107 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 0.11 (1107 hom., cov: 30)
• Consequence: PDE11A NM_016953.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.155
• Publications: 32 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 (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE11A	NM_016953.4	c.1576+227C>G		intron_variant	Intron 7 of 19	ENST00000286063.11	NP_058649.3
PDE11A	NM_001077197.2	c.826+227C>G		intron_variant	Intron 8 of 20		NP_001070665.1
PDE11A	NM_001077358.2	c.502+227C>G		intron_variant	Intron 6 of 18		NP_001070826.1
PDE11A	NM_001077196.2	c.244+227C>G		intron_variant	Intron 4 of 16		NP_001070664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11	c.1576+227C>G		intron_variant	Intron 7 of 19	1	NM_016953.4	ENSP00000286063.5

Frequencies

GnomAD3 genomes AF: 0.113 AC: 16946 AN: 150398 Hom.: 1103 Cov.: 30

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0868

Gnomad ASJ AF: 0.0747

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0910

Gnomad FIN AF: 0.0634

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0818

Gnomad OTH AF: 0.119

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

GnomAD4 genome AF: 0.113 AC: 16965 AN: 150514 Hom.: 1107 Cov.: 30 AF XY: 0.110 AC XY: 8099 AN XY: 73436

African (AFR) AF: 0.192 AC: 7852 AN: 40942

American (AMR) AF: 0.0866 AC: 1306 AN: 15074

Ashkenazi Jewish (ASJ) AF: 0.0747 AC: 258 AN: 3456

East Asian (EAS) AF: 0.111 AC: 569 AN: 5118

South Asian (SAS) AF: 0.0914 AC: 436 AN: 4772

European-Finnish (FIN) AF: 0.0634 AC: 654 AN: 10318

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.0818 AC: 5523 AN: 67530

Other (OTH) AF: 0.119 AC: 249 AN: 2098

Alfa AF: 0.0744 Hom.: 287

Bravo AF: 0.117

Asia WGS AF: 0.0910 AC: 317 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	1.5
DANN	Benign	0.39
PhyloP100		0.15
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: rs7567851; hg19: chr2-178684720;