rs41317304

Positions:

• chr14-50924122-C-T

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: -0.519

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGL	NM_002863.5	c.529-22G>A		intron_variant		ENST00000216392.8
PYGL	NM_001163940.2	c.427-22G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGL	ENST00000216392.8	c.529-22G>A		intron_variant		1	NM_002863.5	P1
PYGL	ENST00000532462.5	c.529-22G>A		intron_variant		1
PYGL	ENST00000530336.2	n.596-22G>A		intron_variant, non_coding_transcript_variant		1
PYGL	ENST00000544180.6	c.427-22G>A		intron_variant		2

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

GnomAD3 exomes AF: 0.0403 AC: 10123 AN: 251058 Hom.: 306 AF XY: 0.0402 AC XY: 5453 AN XY: 135702

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 SAS exome AF: 0.0392

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

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.0185

Gnomad4 ASJ exome AF: 0.0354

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0395

Gnomad4 FIN exome AF: 0.0503

Gnomad4 NFE exome AF: 0.0371

Gnomad4 OTH exome AF: 0.0393

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

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0243

Gnomad4 ASJ AF: 0.0331

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0307

Gnomad4 FIN AF: 0.0551

Gnomad4 NFE AF: 0.0397

Gnomad4 OTH AF: 0.0407

Alfa AF: 0.0494 Hom.: 44

Bravo AF: 0.0583

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2021	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 12, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.6
DANN	Benign	0.77

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

LitVar

Other links and lift over

dbSNP: rs41317304; hg19: chr14-51390840;