Genetic Variant NM_002862.4:c.170C>G (chr20-25248348-C-G) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS2

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.52

Publications

9 publications found

Variant links:

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]

PYGB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: Cadd, Eigen, M_CAP, MutationAssessor, PrimateAI, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

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 VariationId is 718469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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.170C>G	p.Ala57Gly	missense	Exon 1 of 20	NP_002853.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PYGB	ENST00000216962.9	TSL:1 MANE Select	c.170C>G	p.Ala57Gly	missense	Exon 1 of 20	ENSP00000216962.3	P11216
PYGB	ENST00000896654.1		c.170C>G	p.Ala57Gly	missense	Exon 1 of 21	ENSP00000566713.1
PYGB	ENST00000944638.1		c.170C>G	p.Ala57Gly	missense	Exon 1 of 21	ENSP00000614697.1

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

352

AN:

152118

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00213

AC:

502

AN:

235882

AF XY:

0.00226

show subpopulations

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 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.:

Cov.:

AF XY:

0.00381

AC XY:

2746

AN XY:

720992

show subpopulations

African (AFR)

AF:

0.000525

AC:

AN:

32380

American (AMR)

AF:

0.000789

AC:

AN:

43108

Ashkenazi Jewish (ASJ)

AF:

0.00390

AC:

101

AN:

25922

East Asian (EAS)

AF:

0.00

AC:

AN:

38710

South Asian (SAS)

AF:

0.00101

AC:

AN:

84484

European-Finnish (FIN)

AF:

0.000594

AC:

AN:

52188

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00472

AC:

5221

AN:

1107088

Other (OTH)

AF:

0.00423

AC:

254

AN:

59998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

367

733

1100

1466

1833

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

214

428

642

856

1070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00231

AC:

352

AN:

152234

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

149

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000625

AC:

AN:

41570

American (AMR)

AF:

0.000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000827

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00429

AC:

292

AN:

67988

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00340

Hom.:

Bravo

AF:

0.00229

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.00211

AC:

256

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.057

MetaSVM

Uncertain

0.35

MutationAssessor

Pathogenic

3.2

PhyloP100

7.5

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.69

Sift

Uncertain

0.020

Sift4G

Uncertain

0.027

Polyphen

0.98

Vest4

0.70

MVP

0.91

MPC

0.25

ClinPred

0.036

GERP RS

4.1

PromoterAI

-0.094

Neutral

(source)

Varity_R

0.87

gMVP

0.64

Mutation Taster

=57/43

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over