20-25295121-AT-ATT

Variant names:

• chr20-25295121-A-AT
• rs148956025
• NM_002862.4:c.2313-481dupT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002862.4(PYGB):​c.2313-481dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,202,884 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: PYGB NM_002862.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.248
• Publications: 0 publications found

Genes affected

PYGB (HGNC:9723): (glycogen phosphorylase B) The protein encoded by this gene is a glycogen phosphorylase found predominantly in the brain. The encoded protein forms homodimers which can associate into homotetramers, the enzymatically active form of glycogen phosphorylase. The activity of this enzyme is positively regulated by AMP and negatively regulated by ATP, ADP, and glucose-6-phosphate. This enzyme catalyzes the rate-determining step in glycogen degradation. [provided by RefSeq, Jul 2008]

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]

ABHD12 Gene-Disease associations (from GenCC):

• PHARC syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002862.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGB	NM_002862.4	MANE Select	c.2313-481dupT		intron	N/A	NP_002853.2
	ABHD12	NM_015600.5		c.1158-92dupA		intron	N/A	NP_056415.1	Q8N2K0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGB	ENST00000216962.9	TSL:1 MANE Select	c.2313-483_2313-482insT		intron	N/A	ENSP00000216962.3	P11216
	ABHD12	ENST00000376542.8	TSL:1	c.1158-92_1158-91insA		intron	N/A	ENSP00000365725.3	Q8N2K0-2
	PYGB	ENST00000896654.1		c.2448-483_2448-482insT		intron	N/A	ENSP00000566713.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000166 AC: 2 AN: 1202884 Hom.: 0 AF XY: 0.00000164 AC XY: 1 AN XY: 611038

African (AFR) AF: 0.00 AC: 0 AN: 28236

American (AMR) AF: 0.00 AC: 0 AN: 44180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24468

East Asian (EAS) AF: 0.00 AC: 0 AN: 38536

South Asian (SAS) AF: 0.00 AC: 0 AN: 80866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5288

European-Non Finnish (NFE) AF: 0.00000228 AC: 2 AN: 876444

Other (OTH) AF: 0.00 AC: 0 AN: 51826

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs148956025; hg19: chr20-25275757;