rs202186644

Variant names:

• chr20-25295668-C-T
• rs202186644
• NM_002862.4:c.2377C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3 BP6_Moderate BS2

The NM_002862.4(PYGB):​c.2377C>T​(p.Arg793Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000829 in 1,613,006 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R793Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00087 (18 hom.)
• Consequence: PYGB NM_002862.4 missense, splice_region
• Scores: Splicing: ADA: 0.9873
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.424
• Publications: 4 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: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 20-25295668-C-T is Benign according to our data. Variant chr20-25295668-C-T is described in ClinVar as Benign. ClinVar VariationId is 3770769.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 18 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.2377C>T	p.Arg793Trp	missense splice_region	Exon 19 of 20	NP_002853.2
	ABHD12	NM_015600.5		c.1158-638G>A		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.2377C>T	p.Arg793Trp	missense splice_region	Exon 19 of 20	ENSP00000216962.3	P11216
	ABHD12	ENST00000376542.8	TSL:1	c.1158-638G>A		intron	N/A	ENSP00000365725.3	Q8N2K0-2
	PYGB	ENST00000896654.1		c.2512C>T	p.Arg838Trp	missense splice_region	Exon 20 of 21	ENSP00000566713.1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152252 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00190 AC: 477 AN: 251410 AF XY: 0.00269

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000872 AC: 1273 AN: 1460636 Hom.: 18 Cov.: 37 AF XY: 0.00127 AC XY: 923 AN XY: 726728

African (AFR) AF: 0.0000299 AC: 1 AN: 33456

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.0136 AC: 1172 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1110998

Other (OTH) AF: 0.000978 AC: 59 AN: 60358

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152370 Hom.: 0 Cov.: 35 AF XY: 0.000658 AC XY: 49 AN XY: 74518

African (AFR) AF: 0.0000240 AC: 1 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15312

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

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

South Asian (SAS) AF: 0.0126 AC: 61 AN: 4830

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00208 AC: 252

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: 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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	0.16
Eigen_PC	Benign	0.057
FATHMM_MKL	Benign	0.38	N
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.42
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.96	D
Vest4		0.34
MutPred		0.47		Gain of catalytic residue at L791 (P = 0.0075)
MVP		0.94
MPC		0.73
ClinPred		0.11	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.59
gMVP		0.57
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.73
SpliceAI score (max)		0.020		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: rs202186644; hg19: chr20-25276304; COSMIC: COSV53820694; COSMIC: COSV53820694;