20-25248348-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002862.4(PYGB):c.170C>G(p.Ala57Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,601,856 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0040 (18 hom.)
• Consequence: PYGB NM_002862.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.52

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056764275).
• BP6: Variant 20-25248348-C-G is Benign according to our data. Variant chr20-25248348-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 718469.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGB	NM_002862.4	c.170C>G	p.Ala57Gly	missense_variant	1/20	ENST00000216962.9
PYGB	XM_047440342.1	c.170C>G	p.Ala57Gly	missense_variant	1/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGB	ENST00000216962.9	c.170C>G	p.Ala57Gly	missense_variant	1/20	1	NM_002862.4	P1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 352 AN: 152118 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00429

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00213 AC: 502 AN: 235882 Hom.: 2 AF XY: 0.00226 AC XY: 290 AN XY: 128436

Gnomad AFR exome AF: 0.000416

Gnomad AMR exome AF: 0.000533

Gnomad ASJ exome AF: 0.00389

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000696

Gnomad FIN exome AF: 0.000786

Gnomad NFE exome AF: 0.00364

Gnomad OTH exome AF: 0.00211

GnomAD4 exome AF: 0.00396 AC: 5745 AN: 1449622 Hom.: 18 Cov.: 32 AF XY: 0.00381 AC XY: 2746 AN XY: 720992

Gnomad4 AFR exome AF: 0.000525

Gnomad4 AMR exome AF: 0.000789

Gnomad4 ASJ exome AF: 0.00390

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.000594

Gnomad4 NFE exome AF: 0.00472

Gnomad4 OTH exome AF: 0.00423

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152234 Hom.: 2 Cov.: 34 AF XY: 0.00200 AC XY: 149 AN XY: 74436

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00429

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00340 Hom.: 2

Bravo AF: 0.00229

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00211 AC: 256

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.057	T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.027	D
Polyphen		0.98	D
Vest4		0.70
MVP		0.91
MPC		0.25
ClinPred		0.036	T
GERP RS		4.1
Varity_R		0.87
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs146966138; hg19: chr20-25228984;