NM_016953.4:c.2761_2763dupTCC

Variant names:

• chr2-177629445-G-GGGA
• rs3830637
• NM_016953.4:c.2761_2763dupTCC

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_016953.4(PDE11A):​c.2761_2763dupTCC​(p.Ser921dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 1,612,458 control chromosomes in the GnomAD database, including 425,175 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (32198 hom., cov: 0)
  • Exomes 𝑓: 0.73 (392977 hom.)
• Consequence: PDE11A NM_016953.4 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.967
• Publications: 15 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 -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_016953.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-177629445-G-GGGA is Benign according to our data. Variant chr2-177629445-G-GGGA is described in ClinVar as Benign. ClinVar VariationId is 1230360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.736 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.2761_2763dupTCC	p.Ser921dup	conservative_inframe_insertion	Exon 20 of 20	NP_058649.3
	PDE11A	NM_001077197.2		c.2011_2013dupTCC	p.Ser671dup	conservative_inframe_insertion	Exon 21 of 21	NP_001070665.1	Q9HCR9-2
	PDE11A	NM_001077358.2		c.1687_1689dupTCC	p.Ser563dup	conservative_inframe_insertion	Exon 19 of 19	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.2761_2763dupTCC	p.Ser921dup	conservative_inframe_insertion	Exon 20 of 20	ENSP00000286063.5	Q9HCR9-1
	PDE11A	ENST00000358450.8	TSL:1	c.2011_2013dupTCC	p.Ser671dup	conservative_inframe_insertion	Exon 21 of 21	ENSP00000351232.4	Q9HCR9-2
	PDE11A	ENST00000409504.5	TSL:1	c.1687_1689dupTCC	p.Ser563dup	conservative_inframe_insertion	Exon 19 of 20	ENSP00000386539.1	Q9HCR9-3

Frequencies

GnomAD3 genomes AF: 0.619 AC: 93967 AN: 151790 Hom.: 32188 Cov.: 0

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.641

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.826

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.742

Gnomad OTH AF: 0.635

GnomAD2 exomes AF: 0.709 AC: 178403 AN: 251470 AF XY: 0.708

Gnomad AFR exome AF: 0.289

Gnomad AMR exome AF: 0.829

Gnomad ASJ exome AF: 0.664

Gnomad EAS exome AF: 0.689

Gnomad FIN exome AF: 0.821

Gnomad NFE exome AF: 0.735

Gnomad OTH exome AF: 0.712

GnomAD4 exome AF: 0.729 AC: 1064305 AN: 1460550 Hom.: 392977 Cov.: 37 AF XY: 0.726 AC XY: 527850 AN XY: 726660

African (AFR) AF: 0.279 AC: 9338 AN: 33458

American (AMR) AF: 0.820 AC: 36662 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 17426 AN: 26128

East Asian (EAS) AF: 0.690 AC: 27374 AN: 39694

South Asian (SAS) AF: 0.643 AC: 55467 AN: 86218

European-Finnish (FIN) AF: 0.814 AC: 43493 AN: 53414

Middle Eastern (MID) AF: 0.616 AC: 3470 AN: 5636

European-Non Finnish (NFE) AF: 0.746 AC: 828914 AN: 1110942

Other (OTH) AF: 0.699 AC: 42161 AN: 60344

GnomAD4 genome AF: 0.619 AC: 93990 AN: 151908 Hom.: 32198 Cov.: 0 AF XY: 0.625 AC XY: 46360 AN XY: 74226

African (AFR) AF: 0.301 AC: 12503 AN: 41474

American (AMR) AF: 0.742 AC: 11325 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 2346 AN: 3464

East Asian (EAS) AF: 0.674 AC: 3477 AN: 5162

South Asian (SAS) AF: 0.662 AC: 3188 AN: 4814

European-Finnish (FIN) AF: 0.826 AC: 8709 AN: 10548

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.742 AC: 50346 AN: 67878

Other (OTH) AF: 0.635 AC: 1334 AN: 2102

Alfa AF: 0.671 Hom.: 5927

Asia WGS AF: 0.668 AC: 2321 AN: 3478

EpiCase AF: 0.721

EpiControl AF: 0.723

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
PhyloP100		0.97
Mutation Taster		=76/24	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3830637; hg19: chr2-178494173; COSMIC: COSV53684883;