chr20-25259238-G-T

Variant names:

• chr20-25259238-G-T
• NM_002862.4:c.245G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002862.4(PYGB):​c.245G>T​(p.Arg82Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,435,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PYGB NM_002862.4 missense, splice_region
• Scores: Splicing: ADA: 0.9738
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.89

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGB	NM_002862.4	c.245G>T	p.Arg82Leu	missense_variant, splice_region_variant	Exon 2 of 20	ENST00000216962.9	NP_002853.2
PYGB	XM_047440342.1	c.245G>T	p.Arg82Leu	missense_variant, splice_region_variant	Exon 2 of 16		XP_047296298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGB	ENST00000216962.9	c.245G>T	p.Arg82Leu	missense_variant, splice_region_variant	Exon 2 of 20	1	NM_002862.4	ENSP00000216962.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435832 Hom.: 0 Cov.: 29 AF XY: 0.00000140 AC XY: 1 AN XY: 715812

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.19e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.2	H
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.044	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.54		Loss of disorder (P = 0.0402);
MVP		0.97
MPC		0.80
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.83
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-25239874;