NM_002863.5:c.529-22G>A

Variant names:

• chr14-50924122-C-T
• rs41317304
• NM_002863.5:c.529-22G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002863.5(PYGL):​c.529-22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0402 in 1,610,916 control chromosomes in the GnomAD database, including 1,719 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (379 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1340 hom.)
• Consequence: PYGL NM_002863.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.519
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 14-50924122-C-T is Benign according to our data. Variant chr14-50924122-C-T is described in ClinVar as Benign. ClinVar VariationId is 258845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 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.529-22G>A		intron	N/A	NP_002854.3
	PYGL	NM_001163940.2		c.427-22G>A		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.529-22G>A		intron	N/A	ENSP00000216392.7	P06737-1
	PYGL	ENST00000532462.5	TSL:1	c.529-22G>A		intron	N/A	ENSP00000431657.1	E9PK47
	PYGL	ENST00000530336.2	TSL:1	n.596-22G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0589 AC: 8961 AN: 152056 Hom.: 377 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0243

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.0551

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0403 AC: 10123 AN: 251058 AF XY: 0.0402

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0169

Gnomad ASJ exome AF: 0.0353

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0534

Gnomad NFE exome AF: 0.0412

Gnomad OTH exome AF: 0.0357

GnomAD4 exome AF: 0.0383 AC: 55829 AN: 1458742 Hom.: 1340 Cov.: 30 AF XY: 0.0384 AC XY: 27870 AN XY: 725874

African (AFR) AF: 0.123 AC: 4091 AN: 33364

American (AMR) AF: 0.0185 AC: 829 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0354 AC: 923 AN: 26094

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39642

South Asian (SAS) AF: 0.0395 AC: 3405 AN: 86208

European-Finnish (FIN) AF: 0.0503 AC: 2672 AN: 53110

Middle Eastern (MID) AF: 0.0549 AC: 316 AN: 5756

European-Non Finnish (NFE) AF: 0.0371 AC: 41216 AN: 1109608

Other (OTH) AF: 0.0393 AC: 2369 AN: 60256

GnomAD4 genome AF: 0.0589 AC: 8965 AN: 152174 Hom.: 379 Cov.: 32 AF XY: 0.0587 AC XY: 4369 AN XY: 74410

African (AFR) AF: 0.119 AC: 4934 AN: 41478

American (AMR) AF: 0.0243 AC: 371 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 115 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0307 AC: 148 AN: 4828

European-Finnish (FIN) AF: 0.0551 AC: 584 AN: 10598

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0397 AC: 2700 AN: 68012

Other (OTH) AF: 0.0407 AC: 86 AN: 2114

Alfa AF: 0.0499 Hom.: 74

Bravo AF: 0.0583

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.6
DANN	Benign	0.77
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41317304; hg19: chr14-51390840;