NM_016953.4:c.2531G>C

Variant names:

• chr2-177669524-C-G
• rs911385258
• NM_016953.4:c.2531G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_016953.4(PDE11A):​c.2531G>C​(p.Arg844Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000842 in 1,306,694 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: PDE11A NM_016953.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016953.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE11A	NM_016953.4	MANE Select	c.2531G>C	p.Arg844Pro	missense	Exon 18 of 20	NP_058649.3
	PDE11A	NM_001077197.2		c.1781G>C	p.Arg594Pro	missense	Exon 19 of 21	NP_001070665.1	Q9HCR9-2
	PDE11A	NM_001077358.2		c.1457G>C	p.Arg486Pro	missense	Exon 17 of 19	NP_001070826.1	Q9HCR9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE11A	ENST00000286063.11	TSL:1 MANE Select	c.2531G>C	p.Arg844Pro	missense	Exon 18 of 20	ENSP00000286063.5	Q9HCR9-1
	PDE11A	ENST00000358450.8	TSL:1	c.1781G>C	p.Arg594Pro	missense	Exon 19 of 21	ENSP00000351232.4	Q9HCR9-2
	PDE11A	ENST00000409504.5	TSL:1	c.1457G>C	p.Arg486Pro	missense	Exon 17 of 20	ENSP00000386539.1	Q9HCR9-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000842 AC: 11 AN: 1306694 Hom.: 0 Cov.: 20 AF XY: 0.00000759 AC XY: 5 AN XY: 658868

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30488

American (AMR) AF: 0.0000224 AC: 1 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25192

East Asian (EAS) AF: 0.00 AC: 0 AN: 38928

South Asian (SAS) AF: 0.00 AC: 0 AN: 83200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5498

European-Non Finnish (NFE) AF: 0.0000103 AC: 10 AN: 970700

Other (OTH) AF: 0.00 AC: 0 AN: 55102

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000038643), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.74
Sift	Benign	0.13	T
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.57		Loss of helix (P = 0.079)
MVP		0.93
MPC		0.77
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.76
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs911385258; hg19: chr2-178534252;