PDE10A

protein-coding

phosphodiesterase 10A, the group of Phosphodiesterases

Gene summary

The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase family. It plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This protein can hydrolyze both cAMP and cGMP to the corresponding nucleoside 5' monophosphate, but has higher affinity for cAMP, and is more efficient with cAMP as substrate. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Dec 2011]

MANE transcript

NM_001385079.1

Inheritance

AD, AR

ClinVar variants

P:14U:147B:76

Top phenotype

Striatal degeneration, autosomal dominant 2

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr6:165,327,287-165,988,117

External References & Databases

Ensembl (ENSG00000112541)

Transcript & Mutation Effects

hg38 • Region Span ~660.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

striatal degeneration, autosomal dominant 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014835

Submitter: Ambry Genetics

childhood-onset benign chorea with striatal involvementSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0044332

Submitter: Orphanet

striatal degeneration, autosomal dominant 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014835

Submitter: Labcorp Genetics (formerly Invitae)

infantile-onset generalized dyskinesia with orofacial involvementSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0044637

Submitter: PanelApp Australia

striatal degeneration, autosomal dominant 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014835

Submitter: G2P

striatal degeneration, autosomal dominant 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014835

Submitter: PanelApp Australia

striatal degeneration, autosomal dominant 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014835

Submitter: Genomics England PanelApp

dyskinesia, limb and orofacial, infantile-onsetSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014834

Submitter: Genomics England PanelApp

infantile-onset generalized dyskinesia with orofacial involvementSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044637

Submitter: Labcorp Genetics (formerly Invitae)

dyskinesia, limb and orofacial, infantile-onsetMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014834

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Striatal degeneration, autosomal dominant 2AD/AR

Manifestation: Neurologic

Intervention: Neurologic

Rationale: In Striatal degeneration, autosomal dominant 2, treatment with levodopa has been described as beneficial in some individuals who developed Parkinsonism

Refs: 27058446; 27058447

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PDE10A variants in ClinVar

9 Conditions Cataloged

not providedTotal: 237

Inborn genetic diseasesTotal: 43

not specifiedTotal: 38

PDE10A-related disorderTotal: 19

Infantile-onset generalized dyskinesia with orofacial involvementTotal: 18

Striatal degeneration, autosomal dominant 2Total: 9

Generalized hypotoniaTotal: 1

Global developmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001385079.1. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	63 clinvar	7 clinvar	75
missense	3 clinvar	5 clinvar	128 clinvar	6 clinvar		142
nonsense	1 clinvar	1 clinvar	5 clinvar			7
start loss						0
frameshift		4 clinvar	5 clinvar			9
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	4	10	147	69	7	237

Highest pathogenic variant AF is 0.0000027533988

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001385079.1	RefSeq	NP_001372008.1	22	MANE Select
ENST00000539869.4	Ensembl	ENSP00000438284.3	22	MANE Select
NM_001130690.3	RefSeq	NP_001124162.1	22	Standard
NM_006661.4	RefSeq	NP_006652.1	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Purine metabolism - Homo sapiens (human)
Morphine addiction - Homo sapiens (human)
Purine Nucleoside Phosphorylase Deficiency
Mercaptopurine Action Pathway
Azathioprine Action Pathway

Biological Process

cAMP catabolic process
G protein-coupled receptor signaling pathway
regulation of protein kinase A signaling
negative regulation of cGMP-mediated signaling
negative regulation of cAMP-mediated signaling

Molecular Function

3',5'-cyclic-nucleotide phosphodiesterase activity
3',5'-cyclic-AMP phosphodiesterase activity
cGMP-stimulated cyclic-nucleotide phosphodiesterase activity
cAMP binding
cGMP binding

Cellular Component

cytosol
membrane
perikaryon

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000539869
Coding exons: 22
Length: 659316
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125748
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.76	222	445	0.499	0.0000241	5200
Missense (PolyPhen)		54	166.1	0.32511		1936
Synonymous	0.258	156	160	0.974	0.00000901	1462
Loss of Function	5.51	4	43.0	0.0931	0.00000200	547

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate. May play a critical role in regulating cAMP and cGMP levels in the striatum, a region of the brain that contributes to the control of movement and cognition. {ECO:0000250|UniProtKB:Q8CA95, ECO:0000269|PubMed:17389385}.;
Disease: DISEASE: Dyskinesia, limb and orofacial, infantile-onset (IOLOD) [MIM:616921]: An autosomal recessive, early-onset hyperkinetic movement disorder characterized by axial hypotonia, dyskinesia of the limbs and trunk, orofacial dyskinesia, drooling, and dysarthria. The severity of the hyperkinesis is variable. {ECO:0000269|PubMed:27058446}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Striatal degeneration, autosomal dominant 2 (ADSD2) [MIM:616922]: An autosomal dominant disorder characterized by striatal degeneration and dysfunction of basal ganglia, resulting in hyperkinesis. {ECO:0000269|PubMed:27058447}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.149

Intolerance Scores

LoFtool: 0.378
RVIS EVS: -0.98
RVIS percentile EVS: 8.8

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.733

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium