rs34096980

Positions:

• chr14-50924018-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002863.5(PYGL):​c.611A>G​(p.Tyr204Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00299 in 1,613,930 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (13 hom.)
• Consequence: PYGL NM_002863.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 6.28

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.059922606).
• BP6: Variant 14-50924018-T-C is Benign according to our data. Variant chr14-50924018-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 313331.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGL	NM_002863.5	c.611A>G	p.Tyr204Cys	missense_variant	5/20	ENST00000216392.8	NP_002854.3
PYGL	NM_001163940.2	c.509A>G	p.Tyr170Cys	missense_variant	4/19		NP_001157412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGL	ENST00000216392.8	c.611A>G	p.Tyr204Cys	missense_variant	5/20	1	NM_002863.5	ENSP00000216392.7
PYGL	ENST00000532462.5	c.611A>G	p.Tyr204Cys	missense_variant	5/20	1		ENSP00000431657.1
PYGL	ENST00000530336.2	n.678A>G		non_coding_transcript_exon_variant	5/5	1
PYGL	ENST00000544180.6	c.509A>G	p.Tyr170Cys	missense_variant	4/19	2		ENSP00000443787.1

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 362 AN: 152216 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00273 AC: 687 AN: 251472 Hom.: 3 AF XY: 0.00274 AC XY: 372 AN XY: 135912

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00337

Gnomad NFE exome AF: 0.00400

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00305 AC: 4461 AN: 1461596 Hom.: 13 Cov.: 30 AF XY: 0.00292 AC XY: 2121 AN XY: 727118

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00373

Gnomad4 NFE exome AF: 0.00351

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.00238 AC: 363 AN: 152334 Hom.: 3 Cov.: 32 AF XY: 0.00235 AC XY: 175 AN XY: 74490

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.00320

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00311 Hom.: 2

Bravo AF: 0.00226

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00315 AC: 382

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00391

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	PYGL: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 08, 2023	BS1, PP3 -

Glycogen storage disease, type VI Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 26, 2017

- -

PYGL-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 25, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	.;.;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.060	T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	.;.;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.9	D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.025	D;D;D
Sift4G	Benign	0.11	T;T;T
Polyphen		1.0	D;.;D
Vest4		0.88
MVP		1.0
MPC		0.60
ClinPred		0.062	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.83
gMVP		0.89

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: rs34096980; hg19: chr14-51390736;