chr20-25300853-G-A
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_ModeratePM2BS1_Supporting
The NM_001042472.3(ABHD12):c.1189C>T(p.Gln397*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000254 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
ABHD12
NM_001042472.3 stop_gained
NM_001042472.3 stop_gained
Scores
4
3
Clinical Significance
Conservation
PhyloP100: 5.75
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 Uncertain_significance. Variant got 3 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00668 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000253 (37/1461766) while in subpopulation MID AF= 0.000694 (4/5764). AF 95% confidence interval is 0.000236. There are 0 homozygotes in gnomad4_exome. There are 23 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000361 AC: 9AN: 249168Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135276
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GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461766Hom.: 0 Cov.: 34 AF XY: 0.0000316 AC XY: 23AN XY: 727186
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GnomAD4 genome 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74370
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 21, 2020 | This sequence change results in a premature translational stop signal in the ABHD12 gene (p.Gln397*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acids of the ABHD12 protein. This variant is present in population databases (rs745990956, ExAC 0.006%). This variant has not been reported in the literature in individuals with ABHD12-related conditions. ClinVar contains an entry for this variant (Variation ID: 191159). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
| Likely benign, criteria provided, single submitter | research | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | - | Downgraded to LB based on updated frequency in local population - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 19, 2025 | Variant summary: ABHD12 c.1189C>T (p.Gln397X) results in a premature termination codon and although it is not predicted to result in absence of the protein due to nonsense mediated decay, it is expected to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. However, variants downstream of this position have not been classified pathogenic in ClinVar or by our lab. The variant allele was found at a frequency of 3.6e-05 in 249168 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1189C>T has been reported in the literature in the homozygous state in an individual with no apparent symptoms of PHARC (Shamia_2015); however, due to the slowly progressive nature of the disorder and variable phenotype, pathogenicity cannot be ruled out. This report does not provide unequivocal conclusions about association of the variant with PHARC syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26141664). ClinVar contains an entry for this variant (Variation ID: 191159). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
PHARC syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 18, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
Source:
Name
Calibrated prediction
Score
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BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at