2-177663913-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_016953.4(PDE11A):c.2599C>T(p.Arg867Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,612,508 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R867G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: PDE11A NM_016953.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38362184).
• BS2: High AC in GnomAd at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE11A	NM_016953.4	c.2599C>T	p.Arg867Trp	missense_variant	19/20	ENST00000286063.11
PDE11A	NM_001077197.2	c.1849C>T	p.Arg617Trp	missense_variant	20/21
PDE11A	NM_001077358.2	c.1525C>T	p.Arg509Trp	missense_variant	18/19
PDE11A	NM_001077196.2	c.1267C>T	p.Arg423Trp	missense_variant	16/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE11A	ENST00000286063.11	c.2599C>T	p.Arg867Trp	missense_variant	19/20	1	NM_016953.4	P1
PDE11A-AS1	ENST00000653062.1	n.365+10130G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000315 AC: 79 AN: 251164 Hom.: 0 AF XY: 0.000273 AC XY: 37 AN XY: 135726

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000171 AC: 250 AN: 1460284 Hom.: 1 Cov.: 28 AF XY: 0.000182 AC XY: 132 AN XY: 726610

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74426

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000863 Hom.: 15

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2023

The c.2599C>T (p.R867W) alteration is located in exon 19 (coding exon 19) of the PDE11A gene. This alteration results from a C to T substitution at nucleotide position 2599, causing the arginine (R) at amino acid position 867 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.8	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	N;D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.012	D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.73
MutPred		0.41		Gain of catalytic residue at R867 (P = 0.0028);.;.;.;
MVP		0.82
MPC		0.63
ClinPred		0.23	T
GERP RS		4.1
Varity_R		0.54
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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;