rs148956025

Variant names:

• chr20-25295121-AT-A
• rs148956025
• NM_002862.4:c.2313-481delT

Your query was ambiguous. Multiple possible variants found:

• chr20-25295121-AT-A
• chr20-25295121-AT-ATT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_002862.4(PYGB):​c.2313-481delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,355,234 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0075 (16 hom., cov: 34)
  • Exomes 𝑓: 0.00074 (13 hom.)
• Consequence: PYGB NM_002862.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.248
• 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 -10 ACMG points.

• BP6: Variant 20-25295121-AT-A is Benign according to our data. Variant chr20-25295121-AT-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1215967.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00746 (1137/152356) while in subpopulation AFR AF = 0.0261 (1086/41582). AF 95% confidence interval is 0.0248. There are 16 homozygotes in GnomAd4. There are 555 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

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.2313-481delT		intron	N/A	NP_002853.2
	ABHD12	NM_015600.5		c.1158-92delA		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.2313-482delT		intron	N/A	ENSP00000216962.3	P11216
	ABHD12	ENST00000376542.8	TSL:1	c.1158-92delA		intron	N/A	ENSP00000365725.3	Q8N2K0-2
	PYGB	ENST00000896654.1		c.2448-482delT		intron	N/A	ENSP00000566713.1

Frequencies

GnomAD3 genomes AF: 0.00747 AC: 1137 AN: 152238 Hom.: 16 Cov.: 34

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.000738 AC: 888 AN: 1202878 Hom.: 13 AF XY: 0.000642 AC XY: 392 AN XY: 611034

African (AFR) AF: 0.0243 AC: 685 AN: 28234

American (AMR) AF: 0.00124 AC: 55 AN: 44180

Ashkenazi Jewish (ASJ) AF: 0.000368 AC: 9 AN: 24468

East Asian (EAS) AF: 0.00 AC: 0 AN: 38536

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53040

Middle Eastern (MID) AF: 0.00170 AC: 9 AN: 5288

European-Non Finnish (NFE) AF: 0.0000434 AC: 38 AN: 876444

Other (OTH) AF: 0.00176 AC: 91 AN: 51822

GnomAD4 genome AF: 0.00746 AC: 1137 AN: 152356 Hom.: 16 Cov.: 34 AF XY: 0.00745 AC XY: 555 AN XY: 74500

African (AFR) AF: 0.0261 AC: 1086 AN: 41582

American (AMR) AF: 0.00222 AC: 34 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68040

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00566 Hom.: 2

Bravo AF: 0.00854

Asia WGS AF: 0.000577 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism

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: rs148956025; hg19: chr20-25275757;