NM_002863.5:c.1828-2delA

Variant names:

• chr14-50911872-CT-C
• rs11356035
• NM_002863.5:c.1828-2delA

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.00
• Publications: 16 publications found

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

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	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.: 0

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

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.: 0 AF XY: 0.372 AC XY: 270277 AN XY: 727164

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

GnomAD4 genome AF: 0.460 AC: 69959 AN: 151982 Hom.: 17685 Cov.: 0 AF XY: 0.464 AC XY: 34462 AN XY: 74294

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

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

Pathogenic	VUS	Benign	Condition
-	-	3	Glycogen storage disease, type VI (3)
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=76/24	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11356035; hg19: chr14-51378590; COSMIC: COSV53585980; COSMIC: COSV53585980;