chr2-177701185-T-C

Variant names:

• chr2-177701185-T-C
• rs17400325
• NM_016953.4:c.2180A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3 BP4_Strong BA1

The NM_016953.4(PDE11A):​c.2180A>G​(p.Tyr727Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0362 in 1,602,844 control chromosomes in the GnomAD database, including 1,255 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.029 (89 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1166 hom.)
• Consequence: PDE11A NM_016953.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67
• Publications: 65 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 -11 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0100132525).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE11A	NM_016953.4	c.2180A>G	p.Tyr727Cys	missense_variant	Exon 14 of 20	ENST00000286063.11	NP_058649.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11	c.2180A>G	p.Tyr727Cys	missense_variant	Exon 14 of 20	1	NM_016953.4	ENSP00000286063.5

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4346 AN: 152098 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.00922

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0453

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0220

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0368

Gnomad OTH AF: 0.0545

GnomAD2 exomes AF: 0.0316 AC: 7928 AN: 250840 AF XY: 0.0329

Gnomad AFR exome AF: 0.00727

Gnomad AMR exome AF: 0.0354

Gnomad ASJ exome AF: 0.0698

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.0393

Gnomad OTH exome AF: 0.0456

GnomAD4 exome AF: 0.0370 AC: 53625 AN: 1450626 Hom.: 1166 Cov.: 28 AF XY: 0.0371 AC XY: 26780 AN XY: 722492

African (AFR) AF: 0.00716 AC: 238 AN: 33240

American (AMR) AF: 0.0367 AC: 1640 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0669 AC: 1744 AN: 26078

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39648

South Asian (SAS) AF: 0.0242 AC: 2077 AN: 85998

European-Finnish (FIN) AF: 0.0194 AC: 1035 AN: 53396

Middle Eastern (MID) AF: 0.0785 AC: 449 AN: 5718

European-Non Finnish (NFE) AF: 0.0400 AC: 44106 AN: 1101880

Other (OTH) AF: 0.0389 AC: 2333 AN: 59984

GnomAD4 genome AF: 0.0285 AC: 4340 AN: 152218 Hom.: 89 Cov.: 32 AF XY: 0.0280 AC XY: 2081 AN XY: 74432

African (AFR) AF: 0.00917 AC: 381 AN: 41558

American (AMR) AF: 0.0452 AC: 690 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 239 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0222 AC: 107 AN: 4812

European-Finnish (FIN) AF: 0.0191 AC: 203 AN: 10612

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0368 AC: 2503 AN: 67986

Other (OTH) AF: 0.0530 AC: 112 AN: 2114

Alfa AF: 0.0364 Hom.: 414

Bravo AF: 0.0304

TwinsUK AF: 0.0450 AC: 167

ALSPAC AF: 0.0449 AC: 173

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0403 AC: 347

ExAC AF: 0.0300 AC: 3643

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0434

EpiControl AF: 0.0497

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.7	H;.;.;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.7	D;D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.80
MPC		0.67
ClinPred		0.065	T
GERP RS		5.7
Varity_R		0.93
gMVP		0.68
Mutation Taster		=81/19	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17400325; hg19: chr2-178565913; COSMIC: COSV107259256;