Genetic Variant NM_016953.4:c.2424-558T>G (chr2-177676076-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_016953.4(PDE11A):c.2424-558T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 192,254 control chromosomes in the GnomAD database, including 8,428 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 0.24 ( 7935 hom., cov: 33)

Exomes 𝑓: 0.13 ( 493 hom. )

Consequence

PDE11A
NM_016953.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.409

Publications

9 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE11A	NM_016953.4 link	c.2424-558T>G		intron_variant	Intron 16 of 19	ENST00000286063.11	NP_058649.3	Q9HCR9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11 link	c.2424-558T>G		intron_variant	Intron 16 of 19	1	NM_016953.4	ENSP00000286063.5		Q9HCR9-1

Frequencies

GnomAD3 genomes

AF:

0.243

AC:

36945

AN:

151982

Hom.:

7919

Cov.:

show subpopulations

Gnomad AFR

AF:

0.578

Gnomad AMI

AF:

0.225

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.124

Gnomad EAS

AF:

0.233

Gnomad SAS

AF:

0.206

Gnomad FIN

AF:

0.0441

Gnomad MID

AF:

0.277

Gnomad NFE

AF:

0.105

Gnomad OTH

AF:

0.220

GnomAD4 exome

AF:

0.126

AC:

5046

AN:

40154

Hom.:

493

Cov.:

AF XY:

0.132

AC XY:

2829

AN XY:

21404

show subpopulations

African (AFR)

AF:

0.564

AC:

461

AN:

818

American (AMR)

AF:

0.107

AC:

377

AN:

3530

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

AN:

750

East Asian (EAS)

AF:

0.195

AC:

563

AN:

2894

South Asian (SAS)

AF:

0.201

AC:

1106

AN:

5512

European-Finnish (FIN)

AF:

0.0575

AC:

AN:

1200

Middle Eastern (MID)

AF:

0.177

AC:

AN:

124

European-Non Finnish (NFE)

AF:

0.0906

AC:

2125

AN:

23452

Other (OTH)

AF:

0.121

AC:

227

AN:

1874

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

200

400

599

799

999

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.243

AC:

37007

AN:

152100

Hom.:

7935

Cov.:

AF XY:

0.238

AC XY:

17701

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.578

AC:

23965

AN:

41440

American (AMR)

AF:

0.136

AC:

2077

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

429

AN:

3468

East Asian (EAS)

AF:

0.233

AC:

1202

AN:

5166

South Asian (SAS)

AF:

0.206

AC:

994

AN:

4820

European-Finnish (FIN)

AF:

0.0441

AC:

468

AN:

10606

Middle Eastern (MID)

AF:

0.264

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.105

AC:

7126

AN:

68006

Other (OTH)

AF:

0.221

AC:

464

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1087

2175

3262

4350

5437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.211

Hom.:

1988

Bravo

AF:

0.264

Asia WGS

AF:

0.226

AC:

786

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

9.3

(source)

DANN

Benign

0.73

PhyloP100

0.41

PromoterAI

0.00090

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over