20-25295254-C-A

Position:

• chr20-25295254-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002862.4(PYGB):​c.2313-350C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 152,212 control chromosomes in the GnomAD database, including 16,015 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.45 (16015 hom., cov: 35)
• Consequence: PYGB NM_002862.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.783

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]

PYGB (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-25295254-C-A is Benign according to our data. Variant chr20-25295254-C-A is described in ClinVar as [Benign]. Clinvar id is 1231287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	Protein	UniProt
PYGB	NM_002862.4	c.2313-350C>A		intron_variant		ENST00000216962.9	NP_002853.2
ABHD12	NM_015600.5	c.1158-224G>T		intron_variant			NP_056415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGB	ENST00000216962.9	c.2313-350C>A		intron_variant		1	NM_002862.4	ENSP00000216962.3

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68410 AN: 152094 Hom.: 16006 Cov.: 35

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.917

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.422

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.450 AC: 68452 AN: 152212 Hom.: 16015 Cov.: 35 AF XY: 0.451 AC XY: 33603 AN XY: 74430

Gnomad4 AFR AF: 0.436

Gnomad4 AMR AF: 0.384

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.918

Gnomad4 SAS AF: 0.475

Gnomad4 FIN AF: 0.451

Gnomad4 NFE AF: 0.442

Gnomad4 OTH AF: 0.424

Alfa AF: 0.305 Hom.: 791

Bravo AF: 0.445

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.38
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2257420; hg19: chr20-25275890;