2-177663913-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_016953.4(PDE11A):c.2599C>G(p.Arg867Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,612,218 control chromosomes in the GnomAD database, including 597 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R867W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.024 (67 hom., cov: 32)
  • Exomes 𝑓: 0.018 (530 hom.)
• Consequence: PDE11A NM_016953.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.38

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042925477).
• BP6: Variant 2-177663913-G-C is Benign according to our data. Variant chr2-177663913-G-C is described in ClinVar as [Benign]. Clinvar id is 1235464.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE11A	NM_016953.4	c.2599C>G	p.Arg867Gly	missense_variant	19/20	ENST00000286063.11
PDE11A	NM_001077197.2	c.1849C>G	p.Arg617Gly	missense_variant	20/21
PDE11A	NM_001077358.2	c.1525C>G	p.Arg509Gly	missense_variant	18/19
PDE11A	NM_001077196.2	c.1267C>G	p.Arg423Gly	missense_variant	16/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE11A	ENST00000286063.11	c.2599C>G	p.Arg867Gly	missense_variant	19/20	1	NM_016953.4	P1
PDE11A-AS1	ENST00000653062.1	n.365+10130G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 3704 AN: 152098 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.0402

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0407

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.0657

Gnomad FIN AF: 0.00896

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0283

GnomAD3 exomes AF: 0.0244 AC: 6130 AN: 251164 Hom.: 156 AF XY: 0.0280 AC XY: 3795 AN XY: 135726

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.0452

Gnomad EAS exome AF: 0.0107

Gnomad SAS exome AF: 0.0751

Gnomad FIN exome AF: 0.00758

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0182 AC: 26627 AN: 1460000 Hom.: 530 Cov.: 28 AF XY: 0.0204 AC XY: 14819 AN XY: 726460

Gnomad4 AFR exome AF: 0.0388

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.0462

Gnomad4 EAS exome AF: 0.00569

Gnomad4 SAS exome AF: 0.0761

Gnomad4 FIN exome AF: 0.00702

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0227

GnomAD4 genome AF: 0.0244 AC: 3709 AN: 152218 Hom.: 67 Cov.: 32 AF XY: 0.0247 AC XY: 1839 AN XY: 74426

Gnomad4 AFR AF: 0.0402

Gnomad4 AMR AF: 0.0165

Gnomad4 ASJ AF: 0.0407

Gnomad4 EAS AF: 0.00984

Gnomad4 SAS AF: 0.0656

Gnomad4 FIN AF: 0.00896

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0149 Hom.: 15

Bravo AF: 0.0243

TwinsUK AF: 0.0167 AC: 62

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.0431 AC: 190

ESP6500EA AF: 0.0173 AC: 149

ExAC AF: 0.0253 AC: 3067

EpiCase AF: 0.0202

EpiControl AF: 0.0215

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 20, 2020

This variant is associated with the following publications: (PMID: 17178847, 25525159, 23771924, 21047926, 18559625) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;.;.
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	D;D;D;D
MetaRNN	Benign	0.0043	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.24	N;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.39	T;T;T;T
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.0010	B;.;.;B
Vest4		0.37
MPC		0.19
ClinPred		0.014	T
GERP RS		4.1
Varity_R		0.27
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs61306957; hg19: chr2-178528641; COSMIC: COSV53698312;