14-50944251-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002863.5(PYGL):c.153C>T(p.Asp51Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 1,613,776 control chromosomes in the GnomAD database, including 2,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 541 hom., cov: 33)

Exomes 𝑓: 0.039 ( 1480 hom. )

Consequence

PYGL
NM_002863.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.27

Publications

6 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 14-50944251-G-A is Benign according to our data. Variant chr14-50944251-G-A is described in ClinVar as Benign. ClinVar VariationId is 193236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGL	NM_002863.5 link	c.153C>T	p.Asp51Asp	synonymous_variant	Exon 1 of 20	ENST00000216392.8	NP_002854.3	P06737-1
PYGL	NM_001163940.2 link	c.153C>T	p.Asp51Asp	synonymous_variant	Exon 1 of 19		NP_001157412.1	P06737-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PYGL	ENST00000216392.8 link	c.153C>T	p.Asp51Asp	synonymous_variant	Exon 1 of 20	1	NM_002863.5	ENSP00000216392.7	P06737-1
PYGL	ENST00000532462.5 link	c.153C>T	p.Asp51Asp	synonymous_variant	Exon 1 of 20	1		ENSP00000431657.1	E9PK47
PYGL	ENST00000530336.2 link	n.220C>T		non_coding_transcript_exon_variant	Exon 1 of 5	1
PYGL	ENST00000544180.6 link	c.153C>T	p.Asp51Asp	synonymous_variant	Exon 1 of 19	2		ENSP00000443787.1	P06737-2

Frequencies

GnomAD3 genomes

AF:

0.0676

AC:

10292

AN:

152214

Hom.:

537

Cov.:

show subpopulations

Gnomad AFR

AF:

0.149

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0288

Gnomad ASJ

AF:

0.0323

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0318

Gnomad FIN

AF:

0.0549

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0394

Gnomad OTH

AF:

0.0517

GnomAD2 exomes

AF:

0.0426

AC:

10679

AN:

250590

AF XY:

0.0418

show subpopulations

Gnomad AFR exome

AF:

0.155

Gnomad AMR exome

AF:

0.0179

Gnomad ASJ exome

AF:

0.0342

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0533

Gnomad NFE exome

AF:

0.0408

Gnomad OTH exome

AF:

0.0365

GnomAD4 exome

AF:

0.0393

AC:

57387

AN:

1461444

Hom.:

1480

Cov.:

AF XY:

0.0392

AC XY:

28503

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.157

AC:

5266

AN:

33470

American (AMR)

AF:

0.0198

AC:

885

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0347

AC:

906

AN:

26118

East Asian (EAS)

AF:

0.000202

AC:

AN:

39692

South Asian (SAS)

AF:

0.0400

AC:

3448

AN:

86256

European-Finnish (FIN)

AF:

0.0505

AC:

2683

AN:

53180

Middle Eastern (MID)

AF:

0.0515

AC:

297

AN:

5768

European-Non Finnish (NFE)

AF:

0.0373

AC:

41427

AN:

1111866

Other (OTH)

AF:

0.0409

AC:

2467

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

3723

7446

11170

14893

18616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1524

3048

4572

6096

7620

<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:

0.0677

AC:

10312

AN:

152332

Hom.:

541

Cov.:

AF XY:

0.0666

AC XY:

4959

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.149

AC:

6212

AN:

41564

American (AMR)

AF:

0.0288

AC:

441

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0323

AC:

112

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.0323

AC:

156

AN:

4832

European-Finnish (FIN)

AF:

0.0549

AC:

583

AN:

10626

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0394

AC:

2679

AN:

68030

Other (OTH)

AF:

0.0511

AC:

108

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

481

962

1443

1924

2405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0444

Hom.:

331

Bravo

AF:

0.0690

Asia WGS

AF:

0.0240

AC:

AN:

3478

EpiCase

AF:

0.0368

EpiControl

AF:

0.0378

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 12, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 26, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Apr 06, 2015

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

- -

Glycogen storage disease, type VI

Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

2.3

PromoterAI

0.012

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=99/1

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

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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