2-177663880-T-G

Variant names:

• chr2-177663880-T-G
• rs74357545
• NM_016953.4:c.2632A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_016953.4(PDE11A):​c.2632A>C​(p.Met878Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,589,854 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M878V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (3 hom.)
• Consequence: PDE11A NM_016953.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45
• Publications: 23 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021505088).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000788 (120/152326) while in subpopulation AFR AF = 0.00279 (116/41560). AF 95% confidence interval is 0.00238. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 120 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE11A	NM_016953.4	c.2632A>C	p.Met878Leu	missense_variant	Exon 19 of 20	ENST00000286063.11	NP_058649.3
PDE11A	NM_001077197.2	c.1882A>C	p.Met628Leu	missense_variant	Exon 20 of 21		NP_001070665.1
PDE11A	NM_001077358.2	c.1558A>C	p.Met520Leu	missense_variant	Exon 18 of 19		NP_001070826.1
PDE11A	NM_001077196.2	c.1300A>C	p.Met434Leu	missense_variant	Exon 16 of 17		NP_001070664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11	c.2632A>C	p.Met878Leu	missense_variant	Exon 19 of 20	1	NM_016953.4	ENSP00000286063.5

Frequencies

GnomAD3 genomes AF: 0.000788 AC: 120 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000259 AC: 65 AN: 251106 AF XY: 0.000199

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000107 AC: 154 AN: 1437528 Hom.: 3 Cov.: 27 AF XY: 0.0000851 AC XY: 61 AN XY: 716966

African (AFR) AF: 0.00415 AC: 137 AN: 32980

American (AMR) AF: 0.000134 AC: 6 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 85776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089774

Other (OTH) AF: 0.000184 AC: 11 AN: 59624

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74494

African (AFR) AF: 0.00279 AC: 116 AN: 41560

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00000343 Hom.: 21

Bravo AF: 0.00119

ExAC AF: 0.000313 AC: 38

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Benign	0.67
DEOGEN2	Benign	0.090	T;.;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.64	T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.022	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.39	N;.;.;.
PhyloP100		1.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.23	N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	B;.;.;B
Vest4		0.45
MutPred		0.70		Gain of catalytic residue at M878 (P = 0.0265);.;.;.;
MVP		0.44
MPC		0.17
ClinPred		0.0065	T
GERP RS		3.7
Varity_R		0.084
gMVP		0.34
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs74357545; hg19: chr2-178528608;