rs74357545

Positions:

• chr2-177663880-T-C
• chr2-177663880-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000286063.11(PDE11A):​c.2632A>G​(p.Met878Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,589,640 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (7 hom., cov: 32)
  • Exomes 𝑓: 0.011 (132 hom.)
• Consequence: PDE11A ENST00000286063.11 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.45

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020577222).
• BP6: Variant 2-177663880-T-C is Benign according to our data. Variant chr2-177663880-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 377121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-177663880-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 1032 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE11A	NM_016953.4	c.2632A>G	p.Met878Val	missense_variant	19/20	ENST00000286063.11	NP_058649.3
PDE11A	NM_001077197.2	c.1882A>G	p.Met628Val	missense_variant	20/21		NP_001070665.1
PDE11A	NM_001077358.2	c.1558A>G	p.Met520Val	missense_variant	18/19		NP_001070826.1
PDE11A	NM_001077196.2	c.1300A>G	p.Met434Val	missense_variant	16/17		NP_001070664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11	c.2632A>G	p.Met878Val	missense_variant	19/20	1	NM_016953.4	ENSP00000286063	P1
PDE11A-AS1	ENST00000653062.1	n.365+10097T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00678 AC: 1032 AN: 152210 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00655 AC: 1645 AN: 251106 Hom.: 9 AF XY: 0.00664 AC XY: 901 AN XY: 135688

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00544

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00163

Gnomad FIN exome AF: 0.00314

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00800

GnomAD4 exome AF: 0.0110 AC: 15750 AN: 1437312 Hom.: 132 Cov.: 27 AF XY: 0.0106 AC XY: 7618 AN XY: 716870

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00551

Gnomad4 ASJ exome AF: 0.00242

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00170

Gnomad4 FIN exome AF: 0.00320

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.00677 AC: 1032 AN: 152328 Hom.: 7 Cov.: 32 AF XY: 0.00595 AC XY: 443 AN XY: 74494

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.0119

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00956 Hom.: 13

Bravo AF: 0.00693

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0133 AC: 114

ExAC AF: 0.00649 AC: 788

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0111

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 30, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T;.;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D;D;D;D
MetaRNN	Benign	0.021	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.53	N;.;.;.
MutationTaster	Benign	0.94	N;N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.028	D;D;D;D
Sift4G	Benign	0.071	T;T;T;T
Polyphen		0.027	B;.;.;B
Vest4		0.64
MVP		0.68
MPC		0.19
ClinPred		0.0061	T
GERP RS		3.7
Varity_R		0.18
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs74357545; hg19: chr2-178528608;