rs1555817157

chr20-25339319-ATCTTCCTCAGGCG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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]

ACMG classification

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

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555817157; hg19: chr20-25319955;