ABHD12

protein-coding

abhydrolase domain containing 12, lysophospholipase, the group of Abhydrolase domain containing

Gene summary

This gene encodes an enzyme that catalyzes the hydrolysis of 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors, CB1 and CB2. The endocannabinoid system is involved in a wide range of physiological processes, including neurotransmission, mood, appetite, pain appreciation, addiction behavior, and inflammation. Mutations in this gene are associated with the neurodegenerative disease, PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract), resulting from an inborn error of endocannabinoid metabolism. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Jan 2011]

Previous symbols:

C20orf22

MANE transcript

NM_001042472.3

Inheritance

ClinVar variants

P:67U:227B:110

Top phenotype

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr20:25,294,742-25,390,835

External References & Databases

Ensembl (ENSG00000100997)

Transcript & Mutation Effects

hg38 • Region Span ~96.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

PHARC syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012984

Submitter: Orphanet

PHARC syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012984

Submitter: PanelApp Australia

PHARC syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012984

Submitter: ClinGen

The ABHD12 gene has been associated with autosomal recessive PHARC syndrome using the ClinGen Clinical Validity Framework as of 6/26/18. This association was made using case-level data only. At least 6 variants (nonsense, frameshift, large deletion) have been reported in humans. ABHD12 was first associated with this disease in humans as early as 2010 (Fickerstrand et al.). Association is seen in at least 6 probands in 5 publications (20797687, 25743180, 22938382, 28448692). Variants in this gene segregated with disease in 2 additional family members (20797687). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This gene-disease association is supported by a zebrafish model and additional functional assays. In summary, ABHD12 is definitively associated with autosomal recessive PHARC syndrome. This classification was approved by the ClinGen Hearing Loss Working Group on 6/26/2018.

PHARC syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012984

Submitter: Labcorp Genetics (formerly Invitae)

PHARC syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012984

Submitter: G2P

Clinical Genomic Database (CGD)

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataractAR

Manifestation: Audiologic/Otolaryngologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 19005174; 20797687; 22938382; 24697911

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ABHD12 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 485

ABHD12-related disorderTotal: 75

not specifiedTotal: 71

Inborn genetic diseasesTotal: 63

PHARC syndromeTotal: 53

Retinal dystrophyTotal: 7

Cone dystrophyTotal: 2

Syndromic retinitis pigmentosaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001042472.3. 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			2 clinvar	97 clinvar	2 clinvar	101
missense	2 clinvar	6 clinvar	219 clinvar	10 clinvar	1 clinvar	238
nonsense	14 clinvar	7 clinvar	2 clinvar			23
start loss	1 clinvar					1
frameshift	13 clinvar	10 clinvar	2 clinvar			25
splice donor/acceptor (+/-2bp)	2 clinvar	12 clinvar	2 clinvar			16
Total	32	35	227	107	3	404

Highest pathogenic variant AF is 0.00006763188

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 103 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001042472.3	RefSeq	NP_001035937.1	13	MANE Select
ENST00000339157.10	Ensembl	ENSP00000341408.5	13	MANE Select
NM_015600.5	RefSeq	NP_056415.1	13	Standard
ENST00000376542.8	Ensembl	ENSP00000365725.3	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
abhd12	Danio rerio	Structure: eye photoreceptor cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

abhd12

Danio rerio

Structure: eye photoreceptor cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signaling by GPCR
Signal Transduction
Effects of PIP2 hydrolysis
Platelet activation, signaling and aggregation
Arachidonate production from DAG

Biological Process

protein depalmitoylation
phosphatidylserine catabolic process
adult walking behavior
response to auditory stimulus
acylglycerol catabolic process

Molecular Function

lysophospholipase activity
palmitoyl-(protein) hydrolase activity
acylglycerol lipase activity

Cellular Component

plasma membrane
integral component of membrane
AMPA glutamate receptor complex
dendrite cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000376542
Coding exons: 13
Length: 96241
Individuals with no LoFs: 125712
Homozygous LoFs: 0
Heterozygous LoFs: 36
Defined: 125748
p: 0.000143

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.195	210	218	0.963	0.0000130	2590
Missense (PolyPhen)		59	74.593	0.79096		876
Synonymous	-0.0665	86	85.2	1.01	0.00000556	784
Loss of Function	2.47	12	25.5	0.471	0.00000148	269

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00018	0.00018	rare
South Asian	0.00016	0.00016	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Lysophosphatidylserine (LPS) lipase that plays a key role in the central nervous system. Represents a major LPS lipase in the brain (By similarity). May also have a 2- arachidonoylglycerol (2-AG) hydrolase activity and act as a regulator of endocannabinoid signaling pathways. {ECO:0000250|UniProtKB:Q99LR1, ECO:0000269|PubMed:22969151, ECO:0000269|PubMed:24027063}.;
Disease: DISEASE: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) [MIM:612674]: A slowly progressive neurologic disorder with a variable phenotype resembling Refsum disease. Clinical features include sensorineural hearing loss, visual problems related to cataracts, retinitis pigmentosa, pes cavus, ataxic and/or spastic gait disturbances with a progressive sensorimotor peripheral neuropathy. Other features include hyporeflexia, hyperreflexia, extensor plantar responses. {ECO:0000269|PubMed:20797687, ECO:0000269|PubMed:22938382, ECO:0000269|PubMed:24027063}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.887
RVIS EVS: -0.16
RVIS percentile EVS: 42.06

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.232

Gene Damage Prediction

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