rs267606624

Positions:

• chr20-25302322-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001042472.3(ABHD12):​c.1054C>T​(p.Arg352*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ABHD12 NM_001042472.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.10

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-25302322-G-A is Pathogenic according to our data. Variant chr20-25302322-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 27.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-25302322-G-A is described in Lovd as [Pathogenic]. Variant chr20-25302322-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABHD12	NM_001042472.3	c.1054C>T	p.Arg352*	stop_gained	12/13	ENST00000339157.10	NP_001035937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABHD12	ENST00000339157.10	c.1054C>T	p.Arg352*	stop_gained	12/13	2	NM_001042472.3	ENSP00000341408.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461264 Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9 AN XY: 726954

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000496 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PHARC syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.1054C>T;p.(Arg352*) variant creates a premature translational stop signal in the ABHD12 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 27; OMIM: 613599.0004; PMID: 20797687) - PS4. This variant is not present in population databases (rs267606624, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Arg352*) was detected in trans with a pathogenic variant (PMID: 20797687) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 10, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 03, 2024	Variant summary: ABHD12 c.1054C>T (p.Arg352X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251386 control chromosomes (gnomAD). c.1054C>T has been reported in the literature in individuals affected with PHARC Syndrome (e.g., Fiskerstrand_2010). These data indicate that the variant is likely to be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 20797687). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	ABHD12: PVS1, PM2, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 05, 2019	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ABHD12 are known to be pathogenic (PMID: 20797687). This variant has been observed in an individual affected with suspected PHARC (Polyneuropathy, Hearing loss, Ataxia, Retinitis pigmentosa, and Cataract) (PMID: 20797687). ClinVar contains an entry for this variant (Variation ID: 27). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg352*) in the ABHD12 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.89	D
Vest4		0.79
GERP RS		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs267606624; hg19: chr20-25282958; COSMIC: COSV99404727; COSMIC: COSV99404727;