rs77316189

Positions:

• chr14-50944251-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002863.5(PYGL):​c.153C>T​(p.Asp51=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 1,613,776 control chromosomes in the GnomAD database, including 2,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (541 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1480 hom.)
• Consequence: PYGL NM_002863.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.27

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 14-50944251-G-A is Benign according to our data. Variant chr14-50944251-G-A is described in ClinVar as [Benign]. Clinvar id is 193236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50944251-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGL	NM_002863.5	c.153C>T	p.Asp51=	synonymous_variant	1/20	ENST00000216392.8
PYGL	NM_001163940.2	c.153C>T	p.Asp51=	synonymous_variant	1/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGL	ENST00000216392.8	c.153C>T	p.Asp51=	synonymous_variant	1/20	1	NM_002863.5	P1
PYGL	ENST00000532462.5	c.153C>T	p.Asp51=	synonymous_variant	1/20	1
PYGL	ENST00000530336.2	n.220C>T		non_coding_transcript_exon_variant	1/5	1
PYGL	ENST00000544180.6	c.153C>T	p.Asp51=	synonymous_variant	1/19	2

Frequencies

GnomAD3 genomes AF: 0.0676 AC: 10292 AN: 152214 Hom.: 537 Cov.: 33

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0288

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0318

Gnomad FIN AF: 0.0549

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0394

Gnomad OTH AF: 0.0517

GnomAD3 exomes AF: 0.0426 AC: 10679 AN: 250590 Hom.: 369 AF XY: 0.0418 AC XY: 5669 AN XY: 135716

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.0179

Gnomad ASJ exome AF: 0.0342

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0395

Gnomad FIN exome AF: 0.0533

Gnomad NFE exome AF: 0.0408

Gnomad OTH exome AF: 0.0365

GnomAD4 exome AF: 0.0393 AC: 57387 AN: 1461444 Hom.: 1480 Cov.: 32 AF XY: 0.0392 AC XY: 28503 AN XY: 727076

Gnomad4 AFR exome AF: 0.157

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.0347

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0400

Gnomad4 FIN exome AF: 0.0505

Gnomad4 NFE exome AF: 0.0373

Gnomad4 OTH exome AF: 0.0409

GnomAD4 genome AF: 0.0677 AC: 10312 AN: 152332 Hom.: 541 Cov.: 33 AF XY: 0.0666 AC XY: 4959 AN XY: 74496

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.0288

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0323

Gnomad4 FIN AF: 0.0549

Gnomad4 NFE AF: 0.0394

Gnomad4 OTH AF: 0.0511

Alfa AF: 0.0516 Hom.: 149

Bravo AF: 0.0690

Asia WGS AF: 0.0240 AC: 83 AN: 3478

EpiCase AF: 0.0368

EpiControl AF: 0.0378

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2015	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2020	- -

Glycogen storage disease, type VI Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs77316189; hg19: chr14-51410969; COSMIC: COSV53584774;