chr20-25278370-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 32 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]

ACMG classification

Our verdict: Benign. The variant received -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.

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.907G>T	p.Ala303Ser	missense	Exon 8 of 20	NP_002853.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGB	ENST00000216962.9	TSL:1 MANE Select	c.907G>T	p.Ala303Ser	missense	Exon 8 of 20	ENSP00000216962.3
	PYGB	ENST00000896654.1		c.1042G>T	p.Ala348Ser	missense	Exon 9 of 21	ENSP00000566713.1
	PYGB	ENST00000944638.1		c.907G>T	p.Ala303Ser	missense	Exon 8 of 21	ENSP00000614697.1

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

GnomAD2 exomes AF: 0.169 AC: 42417 AN: 251260 AF XY: 0.164

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 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

African (AFR) AF: 0.0755 AC: 2528 AN: 33478

American (AMR) AF: 0.145 AC: 6503 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0925 AC: 2418 AN: 26134

East Asian (EAS) AF: 0.329 AC: 13079 AN: 39696

South Asian (SAS) AF: 0.109 AC: 9441 AN: 86248

European-Finnish (FIN) AF: 0.189 AC: 10112 AN: 53398

Middle Eastern (MID) AF: 0.117 AC: 673 AN: 5762

European-Non Finnish (NFE) AF: 0.182 AC: 202505 AN: 1111952

Other (OTH) AF: 0.178 AC: 10740 AN: 60390

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

African (AFR) AF: 0.0774 AC: 3218 AN: 41554

American (AMR) AF: 0.156 AC: 2392 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0971 AC: 337 AN: 3470

East Asian (EAS) AF: 0.344 AC: 1767 AN: 5142

South Asian (SAS) AF: 0.107 AC: 515 AN: 4814

European-Finnish (FIN) AF: 0.193 AC: 2043 AN: 10604

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 12964 AN: 67978

Other (OTH) AF: 0.146 AC: 309 AN: 2112

Alfa AF: 0.162 Hom.: 2317

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 v4.9

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
PhyloP100		9.8
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
Mutation Taster		=73/27	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2228976; hg19: chr20-25259006; COSMIC: COSV53816254;