14-50911872-CTT-CT

Position:

• chr14-50911872-CTT-CT

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The NM_002863.5(PYGL):​c.1828-2del variant causes a splice acceptor 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.00

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 -14 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.05542453 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 id is 194627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50911872-CT-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGL	NM_002863.5	c.1828-2del		splice_acceptor_variant		ENST00000216392.8
PYGL	NM_001163940.2	c.1726-2del		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGL	ENST00000216392.8	c.1828-2del		splice_acceptor_variant		1	NM_002863.5	P1
PYGL	ENST00000532462.5	c.1828-2del		splice_acceptor_variant		1
PYGL	ENST00000544180.6	c.1726-2del		splice_acceptor_variant		2
PYGL	ENST00000532107.2			upstream_gene_variant		5

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

GnomAD3 exomes AF: 0.441 AC: 110756 AN: 251422 Hom.: 26796 AF XY: 0.426 AC XY: 57930 AN XY: 135878

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 SAS exome AF: 0.446

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

Gnomad4 AFR exome AF: 0.670

Gnomad4 AMR exome AF: 0.640

Gnomad4 ASJ exome AF: 0.345

Gnomad4 EAS exome AF: 0.657

Gnomad4 SAS exome AF: 0.443

Gnomad4 FIN exome AF: 0.357

Gnomad4 NFE exome AF: 0.335

Gnomad4 OTH exome AF: 0.398

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

Gnomad4 AFR AF: 0.656

Gnomad4 AMR AF: 0.533

Gnomad4 ASJ AF: 0.329

Gnomad4 EAS AF: 0.623

Gnomad4 SAS AF: 0.447

Gnomad4 FIN AF: 0.360

Gnomad4 NFE AF: 0.339

Gnomad4 OTH AF: 0.453

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

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 5552/12518=44.35% -

Glycogen storage disease, type VI Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Oct 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs11356035; hg19: chr14-51378590;