rs35026927

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP3BP4_ModerateBS1_SupportingBS2

The NM_002863.5(PYGL):c.1900G>C(p.Asp634His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,614,102 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D634E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0042 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0069 ( 47 hom. )

Consequence

PYGL
NM_002863.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8B:3O:2

Conservation

PhyloP100: 7.88

Publications

23 publications found

Variant links:

Genes affected

PYGL (HGNC:9725): (glycogen phosphorylase L) This gene encodes a homodimeric protein that catalyses the cleavage of alpha-1,4-glucosidic bonds to release glucose-1-phosphate from liver glycogen stores. This protein switches from inactive phosphorylase B to active phosphorylase A by phosphorylation of serine residue 15. Activity of this enzyme is further regulated by multiple allosteric effectors and hormonal controls. Humans have three glycogen phosphorylase genes that encode distinct isozymes that are primarily expressed in liver, brain and muscle, respectively. The liver isozyme serves the glycemic demands of the body in general while the brain and muscle isozymes supply just those tissues. In glycogen storage disease type VI, also known as Hers disease, mutations in liver glycogen phosphorylase inhibit the conversion of glycogen to glucose and results in moderate hypoglycemia, mild ketosis, growth retardation and hepatomegaly. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Feb 2011]

PYGL Gene-Disease associations (from GenCC):

glycogen storage disease VI
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

PYGL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.08306286).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00425 (647/152322) while in subpopulation NFE AF = 0.00744 (506/68022). AF 95% confidence interval is 0.0069. There are 2 homozygotes in GnomAd4. There are 264 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002863.5. 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
	PYGL	NM_002863.5	MANE Select	c.1900G>C	p.Asp634His	missense	Exon 16 of 20	NP_002854.3
	PYGL	NM_001163940.2		c.1798G>C	p.Asp600His	missense	Exon 15 of 19	NP_001157412.1	P06737-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PYGL	ENST00000216392.8	TSL:1 MANE Select	c.1900G>C	p.Asp634His	missense	Exon 16 of 20	ENSP00000216392.7	P06737-1
PYGL	ENST00000532462.5	TSL:1	c.1900G>C	p.Asp634His	missense	Exon 16 of 20	ENSP00000431657.1	E9PK47
PYGL	ENST00000874287.1		c.1915G>C	p.Asp639His	missense	Exon 16 of 20	ENSP00000544346.1

Frequencies

GnomAD3 genomes

AF:

0.00425

AC:

647

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00744

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00373

AC:

939

AN:

251436

AF XY:

0.00356

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00576

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00203

Gnomad NFE exome

AF:

0.00633

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00687

AC:

10040

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00668

AC XY:

4858

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33474

American (AMR)

AF:

0.00143

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

173

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000858

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00215

AC:

115

AN:

53420

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00829

AC:

9215

AN:

1111916

Other (OTH)

AF:

0.00603

AC:

364

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

598

1196

1794

2392

2990

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

366

732

1098

1464

1830

<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:

0.00425

AC:

647

AN:

152322

Hom.:

Cov.:

AF XY:

0.00354

AC XY:

264

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00127

AC:

AN:

41582

American (AMR)

AF:

0.00242

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00744

AC:

506

AN:

68022

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

100

134

167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00621

Hom.:

Bravo

AF:

0.00383

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.00351

AC:

426

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00687

EpiControl

AF:

0.00605

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease, type VI (9)

not provided (4)

PYGL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.083

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.0

PhyloP100

7.9

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MVP

1.0

MPC

0.59

ClinPred

0.16

GERP RS

5.6

Varity_R

0.95

gMVP

0.89

Mutation Taster

=9/91

disease causing

(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