20-25296608-A-G

Variant names:

• chr20-25296608-A-G
• rs9927
• NM_002862.4:c.*86A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002862.4(PYGB):​c.*86A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 1,487,956 control chromosomes in the GnomAD database, including 189,336 homozygotes. 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: 𝑓 0.49 (18703 hom., cov: 33)
  • Exomes 𝑓: 0.50 (170633 hom.)
• Consequence: PYGB NM_002862.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0520
• Publications: 20 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, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGB	NM_002862.4	c.*86A>G		3_prime_UTR_variant	Exon 20 of 20	ENST00000216962.9	NP_002853.2
ABHD12	NM_015600.5	c.1158-1578T>C		intron_variant	Intron 12 of 12		NP_056415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGB	ENST00000216962.9	c.*86A>G		3_prime_UTR_variant	Exon 20 of 20	1	NM_002862.4	ENSP00000216962.3

Frequencies

GnomAD3 genomes AF: 0.488 AC: 74150 AN: 151964 Hom.: 18688 Cov.: 33

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.917

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.493

Gnomad OTH AF: 0.458

GnomAD4 exome AF: 0.498 AC: 664981 AN: 1335874 Hom.: 170633 Cov.: 24 AF XY: 0.497 AC XY: 327419 AN XY: 659022

African (AFR) AF: 0.457 AC: 13972 AN: 30590

American (AMR) AF: 0.338 AC: 12437 AN: 36780

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 7286 AN: 21452

East Asian (EAS) AF: 0.915 AC: 35079 AN: 38322

South Asian (SAS) AF: 0.476 AC: 34520 AN: 72496

European-Finnish (FIN) AF: 0.488 AC: 17738 AN: 36358

Middle Eastern (MID) AF: 0.403 AC: 1609 AN: 3994

European-Non Finnish (NFE) AF: 0.495 AC: 514520 AN: 1040142

Other (OTH) AF: 0.499 AC: 27820 AN: 55740

GnomAD4 genome AF: 0.488 AC: 74207 AN: 152082 Hom.: 18703 Cov.: 33 AF XY: 0.488 AC XY: 36261 AN XY: 74350

African (AFR) AF: 0.465 AC: 19282 AN: 41484

American (AMR) AF: 0.417 AC: 6376 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1176 AN: 3468

East Asian (EAS) AF: 0.918 AC: 4753 AN: 5180

South Asian (SAS) AF: 0.487 AC: 2343 AN: 4816

European-Finnish (FIN) AF: 0.485 AC: 5129 AN: 10576

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.493 AC: 33533 AN: 67964

Other (OTH) AF: 0.460 AC: 970 AN: 2108

Alfa AF: 0.475 Hom.: 21502

Bravo AF: 0.483

Asia WGS AF: 0.688 AC: 2392 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.8
DANN	Benign	0.54
PhyloP100		0.052
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs9927; hg19: chr20-25277244; COSMIC: COSV108039568; COSMIC: COSV108039568;