chr2-177675565-A-G

Variant names:

• chr2-177675565-A-G
• rs3770016
• NM_016953.4:c.2424-47T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_016953.4(PDE11A):​c.2424-47T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 1,452,882 control chromosomes in the GnomAD database, including 478,161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (42058 hom., cov: 31)
  • Exomes 𝑓: 0.82 (436103 hom.)
• Consequence: PDE11A NM_016953.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.37
• Publications: 14 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-AS1 (HGNC:40433): (PDE11A antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 2-177675565-A-G is Benign according to our data. Variant chr2-177675565-A-G is described in ClinVar as Benign. ClinVar VariationId is 1326998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016953.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE11A	NM_016953.4	MANE Select	c.2424-47T>C		intron	N/A	NP_058649.3
	PDE11A	NM_001077197.2		c.1674-47T>C		intron	N/A	NP_001070665.1	Q9HCR9-2
	PDE11A	NM_001077358.2		c.1350-47T>C		intron	N/A	NP_001070826.1	Q9HCR9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE11A	ENST00000286063.11	TSL:1 MANE Select	c.2424-47T>C		intron	N/A	ENSP00000286063.5	Q9HCR9-1
	PDE11A	ENST00000358450.8	TSL:1	c.1674-47T>C		intron	N/A	ENSP00000351232.4	Q9HCR9-2
	PDE11A	ENST00000409504.5	TSL:1	c.1350-47T>C		intron	N/A	ENSP00000386539.1	Q9HCR9-3

Frequencies

GnomAD3 genomes AF: 0.724 AC: 110035 AN: 151976 Hom.: 42051 Cov.: 31

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.895

Gnomad AMR AF: 0.816

Gnomad ASJ AF: 0.834

Gnomad EAS AF: 0.850

Gnomad SAS AF: 0.820

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.796

Gnomad NFE AF: 0.823

Gnomad OTH AF: 0.741

GnomAD2 exomes AF: 0.813 AC: 196619 AN: 241954 AF XY: 0.816

Gnomad AFR exome AF: 0.439

Gnomad AMR exome AF: 0.893

Gnomad ASJ exome AF: 0.829

Gnomad EAS exome AF: 0.860

Gnomad FIN exome AF: 0.866

Gnomad NFE exome AF: 0.822

Gnomad OTH exome AF: 0.814

GnomAD4 exome AF: 0.816 AC: 1061970 AN: 1300788 Hom.: 436103 Cov.: 18 AF XY: 0.817 AC XY: 535214 AN XY: 654984

African (AFR) AF: 0.441 AC: 13273 AN: 30122

American (AMR) AF: 0.884 AC: 38793 AN: 43884

Ashkenazi Jewish (ASJ) AF: 0.828 AC: 20736 AN: 25054

East Asian (EAS) AF: 0.868 AC: 33478 AN: 38584

South Asian (SAS) AF: 0.808 AC: 66401 AN: 82228

European-Finnish (FIN) AF: 0.867 AC: 45928 AN: 52974

Middle Eastern (MID) AF: 0.823 AC: 4498 AN: 5468

European-Non Finnish (NFE) AF: 0.821 AC: 794732 AN: 967504

Other (OTH) AF: 0.803 AC: 44131 AN: 54970

GnomAD4 genome AF: 0.724 AC: 110081 AN: 152094 Hom.: 42058 Cov.: 31 AF XY: 0.729 AC XY: 54225 AN XY: 74342

African (AFR) AF: 0.450 AC: 18647 AN: 41452

American (AMR) AF: 0.816 AC: 12471 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.834 AC: 2896 AN: 3472

East Asian (EAS) AF: 0.850 AC: 4395 AN: 5172

South Asian (SAS) AF: 0.820 AC: 3946 AN: 4814

European-Finnish (FIN) AF: 0.864 AC: 9154 AN: 10596

Middle Eastern (MID) AF: 0.791 AC: 231 AN: 292

European-Non Finnish (NFE) AF: 0.823 AC: 55964 AN: 68000

Other (OTH) AF: 0.741 AC: 1561 AN: 2106

Alfa AF: 0.791 Hom.: 160892

Bravo AF: 0.707

Asia WGS AF: 0.798 AC: 2776 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Pigmented nodular adrenocortical disease, primary, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	14
DANN	Benign	0.71
PhyloP100		1.4
PromoterAI		-0.026	Neutral
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: rs3770016; hg19: chr2-178540293;