rs17123173

Positions:

• chr14-50920940-C-A

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.772+16G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,593,836 control chromosomes in the GnomAD database, including 899 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (74 hom., cov: 32)
  • Exomes 𝑓: 0.027 (825 hom.)
• Consequence: PYGL NM_002863.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0200

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=-0.77).
• BP6: Variant 14-50920940-C-A is Benign according to our data. Variant chr14-50920940-C-A is described in ClinVar as [Benign]. Clinvar id is 258847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGL	NM_002863.5	c.772+16G>T		intron_variant		ENST00000216392.8
PYGL	NM_001163940.2	c.670+16G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGL	ENST00000216392.8	c.772+16G>T		intron_variant		1	NM_002863.5	P1
PYGL	ENST00000532462.5	c.772+16G>T		intron_variant		1
PYGL	ENST00000544180.6	c.670+16G>T		intron_variant		2
PYGL	ENST00000553872.1	n.573+16G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3523 AN: 152180 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.00676

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0484

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.0902

Gnomad SAS AF: 0.0516

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0316 AC: 7930 AN: 251322 Hom.: 238 AF XY: 0.0324 AC XY: 4394 AN XY: 135820

Gnomad AFR exome AF: 0.00769

Gnomad AMR exome AF: 0.0325

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.0985

Gnomad SAS exome AF: 0.0532

Gnomad FIN exome AF: 0.0199

Gnomad NFE exome AF: 0.0225

Gnomad OTH exome AF: 0.0249

GnomAD4 exome AF: 0.0269 AC: 38825 AN: 1441538 Hom.: 825 Cov.: 30 AF XY: 0.0276 AC XY: 19792 AN XY: 718364

Gnomad4 AFR exome AF: 0.00776

Gnomad4 AMR exome AF: 0.0344

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.0514

Gnomad4 FIN exome AF: 0.0207

Gnomad4 NFE exome AF: 0.0229

Gnomad4 OTH exome AF: 0.0274

GnomAD4 genome AF: 0.0232 AC: 3527 AN: 152298 Hom.: 74 Cov.: 32 AF XY: 0.0248 AC XY: 1846 AN XY: 74470

Gnomad4 AFR AF: 0.00693

Gnomad4 AMR AF: 0.0483

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.0900

Gnomad4 SAS AF: 0.0512

Gnomad4 FIN AF: 0.0203

Gnomad4 NFE AF: 0.0216

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.0207 Hom.: 35

Bravo AF: 0.0234

Asia WGS AF: 0.0710 AC: 247 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2021	- -

Glycogen storage disease, type VI Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

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	-0.77
CADD	Benign	1.7
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs17123173; hg19: chr14-51387658;