2-177629445-G-GGGA

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_016953.4(PDE11A):c.2763_2764insTCC(p.Ser921dup) variant causes a 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 inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.967

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE11A	NM_016953.4	c.2763_2764insTCC	p.Ser921dup	inframe_insertion	20/20	ENST00000286063.11
PDE11A	NM_001077196.2	c.1431_1432insTCC	p.Ser477dup	inframe_insertion	17/17
PDE11A	NM_001077197.2	c.2013_2014insTCC	p.Ser671dup	inframe_insertion	21/21
PDE11A	NM_001077358.2	c.1689_1690insTCC	p.Ser563dup	inframe_insertion	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE11A	ENST00000286063.11	c.2763_2764insTCC	p.Ser921dup	inframe_insertion	20/20	1	NM_016953.4	P1

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

GnomAD3 exomes AF: 0.709 AC: 178403 AN: 251470 Hom.: 65416 AF XY: 0.708 AC XY: 96230 AN XY: 135902

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 SAS exome AF: 0.649

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

Gnomad4 AFR exome AF: 0.279

Gnomad4 AMR exome AF: 0.820

Gnomad4 ASJ exome AF: 0.667

Gnomad4 EAS exome AF: 0.690

Gnomad4 SAS exome AF: 0.643

Gnomad4 FIN exome AF: 0.814

Gnomad4 NFE exome AF: 0.746

Gnomad4 OTH exome AF: 0.699

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

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.742

Gnomad4 ASJ AF: 0.677

Gnomad4 EAS AF: 0.674

Gnomad4 SAS AF: 0.662

Gnomad4 FIN AF: 0.826

Gnomad4 NFE AF: 0.742

Gnomad4 OTH AF: 0.635

Alfa AF: 0.671 Hom.: 5927

Asia WGS AF: 0.668 AC: 2321 AN: 3478

EpiCase AF: 0.721

EpiControl AF: 0.723

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 26, 2019

- -

Pigmented nodular adrenocortical disease, primary, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3830637; hg19: chr2-178494173;