20-25295234-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002862.4(PYGB):c.2313-370A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.933 in 152,358 control chromosomes in the GnomAD database, including 66,390 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.93 (66390 hom., cov: 36)
• Consequence: PYGB NM_002862.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.47

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-25295234-A-G is Benign according to our data. Variant chr20-25295234-A-G is described in ClinVar as [Benign]. Clinvar id is 1221566.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGB	NM_002862.4	c.2313-370A>G		intron_variant		ENST00000216962.9
ABHD12	NM_015600.5	c.1158-204T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGB	ENST00000216962.9	c.2313-370A>G		intron_variant		1	NM_002862.4	P1

Frequencies

GnomAD3 genomes AF: 0.933 AC: 142047 AN: 152240 Hom.: 66337 Cov.: 36

Gnomad AFR AF: 0.982

Gnomad AMI AF: 0.920

Gnomad AMR AF: 0.920

Gnomad ASJ AF: 0.945

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.946

Gnomad FIN AF: 0.897

Gnomad MID AF: 0.968

Gnomad NFE AF: 0.905

Gnomad OTH AF: 0.930

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

GnomAD4 genome AF: 0.933 AC: 142160 AN: 152358 Hom.: 66390 Cov.: 36 AF XY: 0.932 AC XY: 69446 AN XY: 74494

Gnomad4 AFR AF: 0.982

Gnomad4 AMR AF: 0.920

Gnomad4 ASJ AF: 0.945

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.945

Gnomad4 FIN AF: 0.897

Gnomad4 NFE AF: 0.905

Gnomad4 OTH AF: 0.930

Alfa AF: 0.918 Hom.: 12991

Bravo AF: 0.937

Asia WGS AF: 0.976 AC: 3396 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	0.51
Dann	Benign	0.35

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: rs2258720; hg19: chr20-25275870;