rs147211684

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.1093-6C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00855 in 1,613,928 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 13 hom., cov: 33)

Exomes 𝑓: 0.0087 ( 142 hom. )

Consequence

PYGL
NM_002863.5 splice_region, intron

Scores

Splicing: ADA: 0.002281

Clinical Significance

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

Conservation

PhyloP100: 0.536

Publications

1 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 (BayesDel_noAF=-0.8).

BP6

Variant 14-50915977-G-T is Benign according to our data. Variant chr14-50915977-G-T is described in ClinVar as Benign. ClinVar VariationId is 193644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0068 (1036/152320) while in subpopulation SAS AF = 0.0284 (137/4832). AF 95% confidence interval is 0.0245. There are 13 homozygotes in GnomAd4. There are 574 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGL	NM_002863.5 link	c.1093-6C>A		splice_region_variant, intron_variant	Intron 9 of 19	ENST00000216392.8	NP_002854.3	P06737-1
PYGL	NM_001163940.2 link	c.991-6C>A		splice_region_variant, intron_variant	Intron 8 of 18		NP_001157412.1	P06737-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PYGL	ENST00000216392.8 link	c.1093-6C>A	splice_region_variant, intron_variant	Intron 9 of 19	1	NM_002863.5	ENSP00000216392.7	P06737-1
PYGL	ENST00000532462.5 link	c.1093-6C>A	splice_region_variant, intron_variant	Intron 9 of 19	1		ENSP00000431657.1	E9PK47
PYGL	ENST00000544180.6 link	c.991-6C>A	splice_region_variant, intron_variant	Intron 8 of 18	2		ENSP00000443787.1	P06737-2
PYGL	ENST00000528757.2 link	n.-37C>A	upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00679

AC:

1034

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.0357

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0279

Gnomad FIN

AF:

0.0113

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00815

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.0109

AC:

2730

AN:

250962

AF XY:

0.0121

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00292

Gnomad ASJ exome

AF:

0.0361

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00954

Gnomad NFE exome

AF:

0.00943

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.00874

AC:

12770

AN:

1461608

Hom.:

142

Cov.:

AF XY:

0.00962

AC XY:

6992

AN XY:

727086

show subpopulations

African (AFR)

AF:

0.000806

AC:

AN:

33480

American (AMR)

AF:

0.00295

AC:

132

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0357

AC:

933

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0305

AC:

2633

AN:

86250

European-Finnish (FIN)

AF:

0.0106

AC:

565

AN:

53170

Middle Eastern (MID)

AF:

0.00902

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00710

AC:

7896

AN:

1111994

Other (OTH)

AF:

0.00878

AC:

530

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

784

1567

2351

3134

3918

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

302

604

906

1208

1510

<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:

0.00680

AC:

1036

AN:

152320

Hom.:

Cov.:

AF XY:

0.00771

AC XY:

574

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41590

American (AMR)

AF:

0.00327

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0357

AC:

124

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0284

AC:

137

AN:

4832

European-Finnish (FIN)

AF:

0.0113

AC:

120

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00815

AC:

554

AN:

67986

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

117

175

234

292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00969

Hom.:

Bravo

AF:

0.00507

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.00938

EpiControl

AF:

0.00812

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type VI

Benign:3

Aug 17, 2021

Fulgent Genetics, Fulgent Genetics

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. -

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Dec 11, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 21, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

8.5

(source)

DANN

Benign

0.81

PhyloP100

0.54

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0023

dbscSNV1_RF

Benign

0.11

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