20-25295159-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002862.4(PYGB):​c.2313-445C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 948,530 control chromosomes in the GnomAD database, including 170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (99 hom., cov: 34)
  • Exomes 𝑓: 0.0025 (71 hom.)
• Consequence: PYGB NM_002862.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-25295159-C-G is Benign according to our data. Variant chr20-25295159-C-G is described in ClinVar as Benign. ClinVar VariationId is 1252428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0687 is higher than 0.05.

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

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3138 AN: 152234 Hom.: 99 Cov.: 34

Gnomad AFR AF: 0.0709

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.00248 AC: 1975 AN: 796178 Hom.: 71 AF XY: 0.00202 AC XY: 847 AN XY: 419468

African (AFR) AF: 0.0675 AC: 1406 AN: 20826

American (AMR) AF: 0.00478 AC: 183 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: 0.000200 AC: 14 AN: 70034

European-Finnish (FIN) AF: 0.0000831 AC: 4 AN: 48134

Middle Eastern (MID) AF: 0.00184 AC: 8 AN: 4358

European-Non Finnish (NFE) AF: 0.000233 AC: 121 AN: 518424

Other (OTH) AF: 0.00619 AC: 239 AN: 38610

GnomAD4 genome AF: 0.0206 AC: 3141 AN: 152352 Hom.: 99 Cov.: 34 AF XY: 0.0195 AC XY: 1450 AN XY: 74492

African (AFR) AF: 0.0708 AC: 2944 AN: 41580

American (AMR) AF: 0.00856 AC: 131 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68042

Other (OTH) AF: 0.0166 AC: 35 AN: 2114

Alfa AF: 0.0159 Hom.: 7

Bravo AF: 0.0240

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.6
DANN	Benign	0.68
PhyloP100		-0.81
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: rs75097410; hg19: chr20-25275795;