14-50911872-CTT-CT

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1

The NM_002863.5(PYGL):c.1828-2delA variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 17685 hom., cov: 0)

Exomes 𝑓: 0.37 ( 107281 hom. )

Consequence

PYGL
NM_002863.5 splice_acceptor, intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 0.00

Publications

16 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, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, Ambry Genetics

PYGL links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_002863.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05581761 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.4, offset of 0 (no position change), new splice context is: gtttgaccttcttccccaAGgct. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BP6

Variant 14-50911872-CT-C is Benign according to our data. Variant chr14-50911872-CT-C is described in ClinVar as Benign. ClinVar VariationId is 194627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

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.1828-2delA		splice_acceptor intron	N/A	NP_002854.3
	PYGL	NM_001163940.2		c.1726-2delA		splice_acceptor intron	N/A	NP_001157412.1	P06737-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PYGL	ENST00000216392.8	TSL:1 MANE Select	c.1828-2delA	splice_acceptor intron	N/A	ENSP00000216392.7	P06737-1
PYGL	ENST00000532462.5	TSL:1	c.1828-2delA	splice_acceptor intron	N/A	ENSP00000431657.1	E9PK47
PYGL	ENST00000874287.1		c.1843-2delA	splice_acceptor intron	N/A	ENSP00000544346.1

Frequencies

GnomAD3 genomes

AF:

0.460

AC:

69868

AN:

151864

Hom.:

17649

Cov.:

show subpopulations

Gnomad AFR

AF:

0.655

Gnomad AMI

AF:

0.228

Gnomad AMR

AF:

0.533

Gnomad ASJ

AF:

0.329

Gnomad EAS

AF:

0.624

Gnomad SAS

AF:

0.448

Gnomad FIN

AF:

0.360

Gnomad MID

AF:

0.472

Gnomad NFE

AF:

0.339

Gnomad OTH

AF:

0.454

GnomAD2 exomes

AF:

0.441

AC:

110756

AN:

251422

AF XY:

0.426

show subpopulations

Gnomad AFR exome

AF:

0.657

Gnomad AMR exome

AF:

0.655

Gnomad ASJ exome

AF:

0.338

Gnomad EAS exome

AF:

0.609

Gnomad FIN exome

AF:

0.359

Gnomad NFE exome

AF:

0.342

Gnomad OTH exome

AF:

0.407

GnomAD4 exome

AF:

0.371

AC:

542589

AN:

1461716

Hom.:

107281

Cov.:

AF XY:

0.372

AC XY:

270277

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.670

AC:

22419

AN:

33478

American (AMR)

AF:

0.640

AC:

28627

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.345

AC:

9004

AN:

26136

East Asian (EAS)

AF:

0.657

AC:

26102

AN:

39700

South Asian (SAS)

AF:

0.443

AC:

38168

AN:

86248

European-Finnish (FIN)

AF:

0.357

AC:

19091

AN:

53406

Middle Eastern (MID)

AF:

0.451

AC:

2603

AN:

5768

European-Non Finnish (NFE)

AF:

0.335

AC:

372531

AN:

1111868

Other (OTH)

AF:

0.398

AC:

24044

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

23232

46464

69697

92929

116161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12306

24612

36918

49224

61530

<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:

0.460

AC:

69959

AN:

151982

Hom.:

17685

Cov.:

AF XY:

0.464

AC XY:

34462

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.656

AC:

27164

AN:

41430

American (AMR)

AF:

0.533

AC:

8145

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.329

AC:

1143

AN:

3472

East Asian (EAS)

AF:

0.623

AC:

3212

AN:

5158

South Asian (SAS)

AF:

0.447

AC:

2156

AN:

4820

European-Finnish (FIN)

AF:

0.360

AC:

3798

AN:

10560

Middle Eastern (MID)

AF:

0.480

AC:

141

AN:

294

European-Non Finnish (NFE)

AF:

0.339

AC:

23037

AN:

67952

Other (OTH)

AF:

0.453

AC:

955

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1762

3523

5285

7046

8808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

624

1248

1872

2496

3120

<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:

0.393

Hom.:

2272

Bravo

AF:

0.484

Asia WGS

AF:

0.542

AC:

1884

AN:

3478

EpiCase

AF:

0.346

EpiControl

AF:

0.350

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease, type VI (3)

not specified (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=76/24

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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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