rs34313873

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002863.5(PYGL):c.2416A>T(p.Ile806Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,614,030 control chromosomes in the GnomAD database, including 274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 14 hom., cov: 32)

Exomes 𝑓: 0.017 ( 260 hom. )

Consequence

PYGL
NM_002863.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 8.02

Publications

15 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp, Orphanet, Ambry Genetics

PYGL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014384419).

BP6

Variant 14-50905520-T-A is Benign according to our data. Variant chr14-50905520-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0122 (1866/152334) while in subpopulation NFE AF = 0.0178 (1208/68026). AF 95% confidence interval is 0.0169. There are 14 homozygotes in GnomAd4. There are 895 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGL	NM_002863.5 link	c.2416A>T	p.Ile806Leu	missense_variant	Exon 20 of 20	ENST00000216392.8	NP_002854.3	P06737-1
PYGL	NM_001163940.2 link	c.2314A>T	p.Ile772Leu	missense_variant	Exon 19 of 19		NP_001157412.1	P06737-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PYGL	ENST00000216392.8 link	c.2416A>T	p.Ile806Leu	missense_variant	Exon 20 of 20	1	NM_002863.5	ENSP00000216392.7	P06737-1
PYGL	ENST00000532462.5 link	c.2379+2751A>T		intron_variant	Intron 19 of 19	1		ENSP00000431657.1	E9PK47
PYGL	ENST00000544180.6 link	c.2314A>T	p.Ile772Leu	missense_variant	Exon 19 of 19	2		ENSP00000443787.1	P06737-2

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1868

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00425

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0121

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.0125

Gnomad SAS

AF:

0.0164

Gnomad FIN

AF:

0.00960

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0178

Gnomad OTH

AF:

0.0119

GnomAD2 exomes

AF:

0.0133

AC:

3351

AN:

251450

AF XY:

0.0138

show subpopulations

Gnomad AFR exome

AF:

0.00326

Gnomad AMR exome

AF:

0.00752

Gnomad ASJ exome

AF:

0.00744

Gnomad EAS exome

AF:

0.0106

Gnomad FIN exome

AF:

0.0115

Gnomad NFE exome

AF:

0.0167

Gnomad OTH exome

AF:

0.0153

GnomAD4 exome

AF:

0.0171

AC:

24955

AN:

1461696

Hom.:

260

Cov.:

AF XY:

0.0171

AC XY:

12468

AN XY:

727150

show subpopulations

African (AFR)

AF:

0.00290

AC:

AN:

33474

American (AMR)

AF:

0.00783

AC:

350

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00777

AC:

203

AN:

26124

East Asian (EAS)

AF:

0.0141

AC:

561

AN:

39688

South Asian (SAS)

AF:

0.0169

AC:

1457

AN:

86254

European-Finnish (FIN)

AF:

0.0122

AC:

651

AN:

53416

Middle Eastern (MID)

AF:

0.00780

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0185

AC:

20519

AN:

1111860

Other (OTH)

AF:

0.0178

AC:

1072

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1347

2694

4040

5387

6734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

782

1564

2346

3128

3910

<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:

0.0122

AC:

1866

AN:

152334

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

895

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00423

AC:

176

AN:

41576

American (AMR)

AF:

0.0121

AC:

185

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

AN:

3472

East Asian (EAS)

AF:

0.0125

AC:

AN:

5184

South Asian (SAS)

AF:

0.0164

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00960

AC:

102

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0178

AC:

1208

AN:

68026

Other (OTH)

AF:

0.0118

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

192

287

383

479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0154

Hom.:

Bravo

AF:

0.0113

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0169

AC:

145

ExAC

AF:

0.0138

AC:

1672

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0158

EpiControl

AF:

0.0154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type VI

Benign:3

Nov 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:2

Feb 10, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PYGL: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

.;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

MetaRNN

Benign

0.014

T;T

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

3.6

.;H

PhyloP100

8.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.63

Sift

Uncertain

0.024

D;D

Sift4G

Uncertain

0.034

D;D

Polyphen

0.0060

.;B

Vest4

0.35

MutPred

0.29

.;Gain of catalytic residue at I806 (P = 0.0913);

MPC

0.16

ClinPred

0.077

GERP RS

6.1

Varity_R

0.85

gMVP

0.82

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over