20-25295159-C-T

Variant names:

• chr20-25295159-C-T
• rs75097410
• NM_002862.4:c.2313-445C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002862.4(PYGB):​c.2313-445C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 796,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000013 (0 hom.)
• Consequence: PYGB NM_002862.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.806
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.2313-445C>T		intron	N/A	NP_002853.2
	ABHD12	NM_015600.5		c.1158-129G>A		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.2313-445C>T		intron	N/A	ENSP00000216962.3	P11216
	ABHD12	ENST00000376542.8	TSL:1	c.1158-129G>A		intron	N/A	ENSP00000365725.3	Q8N2K0-2
	PYGB	ENST00000896654.1		c.2448-445C>T		intron	N/A	ENSP00000566713.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000126 AC: 1 AN: 796190 Hom.: 0 AF XY: 0.00000238 AC XY: 1 AN XY: 419472

African (AFR) AF: 0.00 AC: 0 AN: 20836

American (AMR) AF: 0.00 AC: 0 AN: 38322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21522

East Asian (EAS) AF: 0.00 AC: 0 AN: 35948

South Asian (SAS) AF: 0.00 AC: 0 AN: 70034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4358

European-Non Finnish (NFE) AF: 0.00000193 AC: 1 AN: 518424

Other (OTH) AF: 0.00 AC: 0 AN: 38612

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.76
PhyloP100		-0.81

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: rs75097410; hg19: chr20-25275795;