chr20-25278370-G-T

Variant names:

• chr20-25278370-G-T
• rs2228976
• NM_002862.4:c.907G>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002862.4(PYGB):​c.907G>T​(p.Ala303Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,613,948 control chromosomes in the GnomAD database, including 26,194 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2160 hom., cov: 34)
  • Exomes 𝑓: 0.18 (24034 hom.)
• Consequence: PYGB NM_002862.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.77

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030773282).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGB	NM_002862.4	c.907G>T	p.Ala303Ser	missense_variant	Exon 8 of 20	ENST00000216962.9	NP_002853.2
PYGB	XM_047440342.1	c.907G>T	p.Ala303Ser	missense_variant	Exon 8 of 16		XP_047296298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGB	ENST00000216962.9	c.907G>T	p.Ala303Ser	missense_variant	Exon 8 of 20	1	NM_002862.4	ENSP00000216962.3

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23790 AN: 152058 Hom.: 2155 Cov.: 34

Gnomad AFR AF: 0.0776

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.0971

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.144

GnomAD3 exomes AF: 0.169 AC: 42417 AN: 251260 Hom.: 4012 AF XY: 0.164 AC XY: 22300 AN XY: 135812

Gnomad AFR exome AF: 0.0769

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.0950

Gnomad EAS exome AF: 0.337

Gnomad SAS exome AF: 0.110

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.176 AC: 257999 AN: 1461772 Hom.: 24034 Cov.: 39 AF XY: 0.174 AC XY: 126565 AN XY: 727182

Gnomad4 AFR exome AF: 0.0755

Gnomad4 AMR exome AF: 0.145

Gnomad4 ASJ exome AF: 0.0925

Gnomad4 EAS exome AF: 0.329

Gnomad4 SAS exome AF: 0.109

Gnomad4 FIN exome AF: 0.189

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.178

GnomAD4 genome AF: 0.156 AC: 23796 AN: 152176 Hom.: 2160 Cov.: 34 AF XY: 0.157 AC XY: 11643 AN XY: 74378

Gnomad4 AFR AF: 0.0774

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.0971

Gnomad4 EAS AF: 0.344

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.193

Gnomad4 NFE AF: 0.191

Gnomad4 OTH AF: 0.146

Alfa AF: 0.156 Hom.: 1172

Bravo AF: 0.150

TwinsUK AF: 0.194 AC: 721

ALSPAC AF: 0.177 AC: 683

ESP6500AA AF: 0.0799 AC: 352

ESP6500EA AF: 0.186 AC: 1597

ExAC AF: 0.166 AC: 20204

EpiCase AF: 0.175

EpiControl AF: 0.167

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.9	T
MutationAssessor	Pathogenic	3.5	H
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.030	D
Polyphen		0.97	D
Vest4		0.33
MPC		0.72
ClinPred		0.040	T
GERP RS		3.6
Varity_R		0.87
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs2228976; hg19: chr20-25259006; COSMIC: COSV53816254;