rs1555817157
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001042472.3(ABHD12):c.211_223del(p.Arg71TyrfsTer26) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
ABHD12
NM_001042472.3 frameshift
NM_001042472.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.60
Genes affected
ABHD12 (HGNC:15868): (abhydrolase domain containing 12, lysophospholipase) 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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 20-25339319-ATCTTCCTCAGGCG-A is Pathogenic according to our data. Variant chr20-25339319-ATCTTCCTCAGGCG-A is described in ClinVar as [Pathogenic]. Clinvar id is 430695.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABHD12 | NM_001042472.3 | c.211_223del | p.Arg71TyrfsTer26 | frameshift_variant | 2/13 | ENST00000339157.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABHD12 | ENST00000339157.10 | c.211_223del | p.Arg71TyrfsTer26 | frameshift_variant | 2/13 | 2 | NM_001042472.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461888Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727246
GnomAD4 exome
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727246
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
PHARC syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Unit of Genetics and Genomics of Neuromuscular Diseases, Principe Felipe Research Center | Jun 30, 2017 | The variant ABHD12:c.211_233del, was detected in homozygous in two related patients with PHARC syndrome. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2021 | ClinVar contains an entry for this variant (Variation ID: 430695). This premature translational stop signal has been observed in individual(s) with polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataracts syndrome (PMID: 29571850). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg71Tyrfs*26) in the ABHD12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABHD12 are known to be pathogenic (PMID: 20797687). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at