2-177663913-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.38

Publications

30 publications found

Variant links:

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 links:

PDE11A-AS1 (HGNC:40433): (PDE11A antisense RNA 1)

PDE11A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
PDE11A	NM_016953.4 link	c.2599C>G	p.Arg867Gly	missense_variant	Exon 19 of 20	ENST00000286063.11	NP_058649.3	Q9HCR9-1
PDE11A	NM_001077197.2 link	c.1849C>G	p.Arg617Gly	missense_variant	Exon 20 of 21		NP_001070665.1	Q9HCR9-2
PDE11A	NM_001077358.2 link	c.1525C>G	p.Arg509Gly	missense_variant	Exon 18 of 19		NP_001070826.1	Q9HCR9-3
PDE11A	NM_001077196.2 link	c.1267C>G	p.Arg423Gly	missense_variant	Exon 16 of 17		NP_001070664.1	Q9HCR9-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11 link	c.2599C>G	p.Arg867Gly	missense_variant	Exon 19 of 20	1	NM_016953.4	ENSP00000286063.5		Q9HCR9-1

Frequencies

GnomAD3 genomes

AF:

0.0244

AC:

3704

AN:

152098

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0244

AC:

6130

AN:

251164

AF XY:

0.0280

show subpopulations

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 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.:

AF XY:

0.0204

AC XY:

14819

AN XY:

726460

show subpopulations

African (AFR)

AF:

0.0388

AC:

1298

AN:

33412

American (AMR)

AF:

0.0142

AC:

636

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0462

AC:

1207

AN:

26114

East Asian (EAS)

AF:

0.00569

AC:

226

AN:

39688

South Asian (SAS)

AF:

0.0761

AC:

6558

AN:

86188

European-Finnish (FIN)

AF:

0.00702

AC:

375

AN:

53404

Middle Eastern (MID)

AF:

0.0660

AC:

380

AN:

5760

European-Non Finnish (NFE)

AF:

0.0131

AC:

14579

AN:

1110398

Other (OTH)

AF:

0.0227

AC:

1368

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1174

2347

3521

4694

5868

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0244

AC:

3709

AN:

152218

Hom.:

Cov.:

AF XY:

0.0247

AC XY:

1839

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0402

AC:

1671

AN:

41528

American (AMR)

AF:

0.0165

AC:

252

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0407

AC:

141

AN:

3468

East Asian (EAS)

AF:

0.00984

AC:

AN:

5182

South Asian (SAS)

AF:

0.0656

AC:

316

AN:

4818

European-Finnish (FIN)

AF:

0.00896

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0147

AC:

997

AN:

68014

Other (OTH)

AF:

0.0275

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

176

353

529

706

882

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0149

Hom.:

Bravo

AF:

0.0243

TwinsUK

AF:

0.0167

AC:

ALSPAC

AF:

0.0112

AC:

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 20, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;.;.;.

Eigen

Benign

0.10

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.89

D;D;D;D

MetaRNN

Benign

0.0043

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.24

N;.;.;.

PhyloP100

2.4

PrimateAI

Uncertain

0.67

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

GERP RS

4.1

Varity_R

0.27

gMVP

0.49

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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2-177663913-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over