rs2227891

Variant names:

• chr20-25282133-G-A
• rs2227891
• NM_002862.4:c.1504G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000216962.9(PYGB):​c.1504G>A​(p.Asp502Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,611,656 control chromosomes in the GnomAD database, including 26,114 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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 (2156 hom., cov: 33)
  • Exomes 𝑓: 0.18 (23958 hom.)
• Consequence: PYGB ENST00000216962.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.98
• 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=0.0013472438).
• 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: ENST00000216962.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGB	NM_002862.4	MANE Select	c.1504G>A	p.Asp502Asn	missense	Exon 12 of 20	NP_002853.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGB	ENST00000216962.9	TSL:1 MANE Select	c.1504G>A	p.Asp502Asn	missense	Exon 12 of 20	ENSP00000216962.3

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23774 AN: 152104 Hom.: 2151 Cov.: 33

Gnomad AFR AF: 0.0772

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.0979

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: 42262 AN: 250324 AF XY: 0.164

Gnomad AFR exome AF: 0.0764

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.0945

Gnomad EAS exome AF: 0.336

Gnomad FIN exome AF: 0.187

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.176 AC: 257201 AN: 1459434 Hom.: 23958 Cov.: 32 AF XY: 0.174 AC XY: 126214 AN XY: 726070

African (AFR) AF: 0.0744 AC: 2487 AN: 33436

American (AMR) AF: 0.145 AC: 6495 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0928 AC: 2421 AN: 26100

East Asian (EAS) AF: 0.328 AC: 13001 AN: 39688

South Asian (SAS) AF: 0.110 AC: 9498 AN: 86148

European-Finnish (FIN) AF: 0.189 AC: 10036 AN: 52968

Middle Eastern (MID) AF: 0.115 AC: 607 AN: 5286

European-Non Finnish (NFE) AF: 0.182 AC: 201953 AN: 1110810

Other (OTH) AF: 0.177 AC: 10703 AN: 60306

GnomAD4 genome AF: 0.156 AC: 23778 AN: 152222 Hom.: 2156 Cov.: 33 AF XY: 0.157 AC XY: 11652 AN XY: 74416

African (AFR) AF: 0.0770 AC: 3200 AN: 41544

American (AMR) AF: 0.156 AC: 2383 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0979 AC: 340 AN: 3472

East Asian (EAS) AF: 0.343 AC: 1771 AN: 5156

South Asian (SAS) AF: 0.107 AC: 517 AN: 4824

European-Finnish (FIN) AF: 0.193 AC: 2045 AN: 10614

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

European-Non Finnish (NFE) AF: 0.191 AC: 12962 AN: 67986

Other (OTH) AF: 0.146 AC: 309 AN: 2116

Alfa AF: 0.171 Hom.: 4199

Bravo AF: 0.150

TwinsUK AF: 0.194 AC: 720

ALSPAC AF: 0.178 AC: 685

ESP6500AA AF: 0.0793 AC: 349

ESP6500EA AF: 0.185 AC: 1593

ExAC AF: 0.166 AC: 20195

Asia WGS AF: 0.239 AC: 828 AN: 3478

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	0.15
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		8.0
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.28
Sift	Benign	0.15	T
Sift4G	Benign	0.41	T
Polyphen		0.0090	B
Vest4		0.14
MPC		0.21
ClinPred		0.11	T
GERP RS		3.9
Varity_R		0.30
gMVP		0.48
Mutation Taster		=72/28	polymorphism (auto)

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: rs2227891; hg19: chr20-25262769; COSMIC: COSV53816266; COSMIC: COSV53816266;