rs946616

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002863.5(PYGL):c.664G>A(p.Val222Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0679 in 1,610,242 control chromosomes in the GnomAD database, including 4,607 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.095 ( 925 hom., cov: 32)

Exomes 𝑓: 0.065 ( 3682 hom. )

Consequence

PYGL
NM_002863.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.12

Publications

19 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=0.0017901957).

BP6

Variant 14-50921064-C-T is Benign according to our data. Variant chr14-50921064-C-T is described in ClinVar as Benign. ClinVar VariationId is 258846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGL	NM_002863.5 link	c.664G>A	p.Val222Ile	missense_variant	Exon 6 of 20	ENST00000216392.8	NP_002854.3	P06737-1
PYGL	NM_001163940.2 link	c.562G>A	p.Val188Ile	missense_variant	Exon 5 of 19		NP_001157412.1	P06737-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PYGL	ENST00000216392.8 link	c.664G>A	p.Val222Ile	missense_variant	Exon 6 of 20	1	NM_002863.5	ENSP00000216392.7	P06737-1
PYGL	ENST00000532462.5 link	c.664G>A	p.Val222Ile	missense_variant	Exon 6 of 20	1		ENSP00000431657.1	E9PK47
PYGL	ENST00000544180.6 link	c.562G>A	p.Val188Ile	missense_variant	Exon 5 of 19	2		ENSP00000443787.1	P06737-2
PYGL	ENST00000553872.1 link	n.465G>A		non_coding_transcript_exon_variant	Exon 1 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.0950

AC:

14451

AN:

152086

Hom.:

924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.185

Gnomad AMI

AF:

0.113

Gnomad AMR

AF:

0.0484

Gnomad ASJ

AF:

0.0866

Gnomad EAS

AF:

0.0164

Gnomad SAS

AF:

0.0865

Gnomad FIN

AF:

0.0546

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0649

Gnomad OTH

AF:

0.0786

GnomAD2 exomes

AF:

0.0694

AC:

17431

AN:

251334

AF XY:

0.0693

show subpopulations

Gnomad AFR exome

AF:

0.189

Gnomad AMR exome

AF:

0.0315

Gnomad ASJ exome

AF:

0.0942

Gnomad EAS exome

AF:

0.00745

Gnomad FIN exome

AF:

0.0532

Gnomad NFE exome

AF:

0.0685

Gnomad OTH exome

AF:

0.0697

GnomAD4 exome

AF:

0.0651

AC:

94945

AN:

1458038

Hom.:

3682

Cov.:

AF XY:

0.0662

AC XY:

48018

AN XY:

725638

show subpopulations

African (AFR)

AF:

0.185

AC:

6184

AN:

33348

American (AMR)

AF:

0.0342

AC:

1530

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0903

AC:

2358

AN:

26110

East Asian (EAS)

AF:

0.0357

AC:

1415

AN:

39686

South Asian (SAS)

AF:

0.0931

AC:

8019

AN:

86166

European-Finnish (FIN)

AF:

0.0566

AC:

3025

AN:

53414

Middle Eastern (MID)

AF:

0.0693

AC:

398

AN:

5746

European-Non Finnish (NFE)

AF:

0.0614

AC:

68054

AN:

1108594

Other (OTH)

AF:

0.0657

AC:

3962

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

4108

8217

12325

16434

20542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2526

5052

7578

10104

12630

<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:

0.0950

AC:

14463

AN:

152204

Hom.:

925

Cov.:

AF XY:

0.0929

AC XY:

6916

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.184

AC:

7651

AN:

41498

American (AMR)

AF:

0.0483

AC:

739

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0866

AC:

300

AN:

3466

East Asian (EAS)

AF:

0.0164

AC:

AN:

5178

South Asian (SAS)

AF:

0.0865

AC:

418

AN:

4830

European-Finnish (FIN)

AF:

0.0546

AC:

579

AN:

10614

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0649

AC:

4412

AN:

68010

Other (OTH)

AF:

0.0773

AC:

163

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

658

1315

1973

2630

3288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<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:

0.0740

Hom.:

2143

Bravo

AF:

0.0966

TwinsUK

AF:

0.0566

AC:

210

ALSPAC

AF:

0.0545

AC:

210

ESP6500AA

AF:

0.183

AC:

807

ESP6500EA

AF:

0.0649

AC:

558

ExAC

AF:

0.0759

AC:

9219

Asia WGS

AF:

0.0530

AC:

183

AN:

3478

EpiCase

AF:

0.0653

EpiControl

AF:

0.0694

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 14, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glycogen storage disease, type VI

Benign:2

Jan 12, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

.;.;T

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.8

.;.;L

PhyloP100

4.1

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.86

N;N;N

REVEL

Uncertain

0.38

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.25

T;T;T

Polyphen

0.016

B;.;B

Vest4

0.066

MPC

0.097

ClinPred

0.025

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.29

gMVP

0.57

Mutation Taster

=91/9

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over