chr2-177663901-C-G

Position:

• chr2-177663901-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016953.4(PDE11A):​c.2611G>C​(p.Glu871Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE11A NM_016953.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE11A	NM_016953.4	c.2611G>C	p.Glu871Gln	missense_variant	19/20	ENST00000286063.11	NP_058649.3
PDE11A	NM_001077197.2	c.1861G>C	p.Glu621Gln	missense_variant	20/21		NP_001070665.1
PDE11A	NM_001077358.2	c.1537G>C	p.Glu513Gln	missense_variant	18/19		NP_001070826.1
PDE11A	NM_001077196.2	c.1279G>C	p.Glu427Gln	missense_variant	16/17		NP_001070664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11	c.2611G>C	p.Glu871Gln	missense_variant	19/20	1	NM_016953.4	ENSP00000286063	P1
PDE11A-AS1	ENST00000653062.1	n.365+10118C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

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

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 17, 2023

Variant summary: PDE11A c.2611G>C (p.Glu871Gln) results in a conservative amino acid change located in the 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain (IPR002073) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251192 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2611G>C in individuals affected with Pigmented Nodular Adrenocortical Disease, Primary, 2 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.3	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.57	N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.21	T;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.17	B;.;.;P
Vest4		0.82
MutPred		0.75		Loss of stability (P = 0.1893);.;.;.;
MVP		0.83
MPC		0.52
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.51
gMVP		0.46

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-178528629;