rs15669

chr14-50910056-G-Achr14-50910056-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002863.5(PYGL):c.2016C>T(p.Thr672=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,613,832 control chromosomes in the GnomAD database, including 19,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4367 hom., cov: 33)
  • Exomes 𝑓: 0.13 (15028 hom.)
• Consequence: PYGL NM_002863.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.01

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 14-50910056-G-A is Benign according to our data. Variant chr14-50910056-G-A is described in ClinVar as [Benign]. Clinvar id is 258836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGL	NM_002863.5	c.2016C>T	p.Thr672=	synonymous_variant	17/20	ENST00000216392.8
PYGL	NM_001163940.2	c.1914C>T	p.Thr638=	synonymous_variant	16/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGL	ENST00000216392.8	c.2016C>T	p.Thr672=	synonymous_variant	17/20	1	NM_002863.5	P1
PYGL	ENST00000532462.5	c.2016C>T	p.Thr672=	synonymous_variant	17/20	1
PYGL	ENST00000544180.6	c.1914C>T	p.Thr638=	synonymous_variant	16/19	2
PYGL	ENST00000532107.2	n.189C>T		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31199 AN: 152002 Hom.: 4362 Cov.: 33

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.169

GnomAD3 exomes AF: 0.149 AC: 37481 AN: 251450 Hom.: 3516 AF XY: 0.148 AC XY: 20157 AN XY: 135892

Gnomad AFR exome AF: 0.409

Gnomad AMR exome AF: 0.0872

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.107

Gnomad SAS exome AF: 0.189

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.134 AC: 195900 AN: 1461712 Hom.: 15028 Cov.: 33 AF XY: 0.136 AC XY: 98607 AN XY: 727162

Gnomad4 AFR exome AF: 0.415

Gnomad4 AMR exome AF: 0.0939

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.148

Gnomad4 SAS exome AF: 0.189

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.205 AC: 31229 AN: 152120 Hom.: 4367 Cov.: 33 AF XY: 0.204 AC XY: 15137 AN XY: 74372

Gnomad4 AFR AF: 0.407

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.167

Alfa AF: 0.142 Hom.: 2800

Bravo AF: 0.209

Asia WGS AF: 0.159 AC: 552 AN: 3478

EpiCase AF: 0.123

EpiControl AF: 0.129

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type VI Benign:3

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 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	-0.69
Cadd	Benign	0.0080
Dann	Benign	0.82

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: rs15669; hg19: chr14-51376774; COSMIC: COSV53584806; COSMIC: COSV53584806;