rs34313873

Positions:

• chr14-50905520-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002863.5(PYGL):​c.2416A>T​(p.Ile806Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,614,030 control chromosomes in the GnomAD database, including 274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (14 hom., cov: 32)
  • Exomes 𝑓: 0.017 (260 hom.)
• Consequence: PYGL NM_002863.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 8.02

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 (MetaRNN=0.014384419).
• BP6: Variant 14-50905520-T-A is Benign according to our data. Variant chr14-50905520-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 258841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905520-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0122 (1866/152334) while in subpopulation NFE AF= 0.0178 (1208/68026). AF 95% confidence interval is 0.0169. There are 14 homozygotes in gnomad4. There are 895 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGL	NM_002863.5	c.2416A>T	p.Ile806Leu	missense_variant	20/20	ENST00000216392.8
PYGL	NM_001163940.2	c.2314A>T	p.Ile772Leu	missense_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGL	ENST00000216392.8	c.2416A>T	p.Ile806Leu	missense_variant	20/20	1	NM_002863.5	P1
PYGL	ENST00000532462.5	c.2379+2751A>T		intron_variant		1
PYGL	ENST00000544180.6	c.2314A>T	p.Ile772Leu	missense_variant	19/19	2

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1868 AN: 152216 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.00960

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0178

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.0133 AC: 3351 AN: 251450 Hom.: 24 AF XY: 0.0138 AC XY: 1882 AN XY: 135906

Gnomad AFR exome AF: 0.00326

Gnomad AMR exome AF: 0.00752

Gnomad ASJ exome AF: 0.00744

Gnomad EAS exome AF: 0.0106

Gnomad SAS exome AF: 0.0172

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0171 AC: 24955 AN: 1461696 Hom.: 260 Cov.: 33 AF XY: 0.0171 AC XY: 12468 AN XY: 727150

Gnomad4 AFR exome AF: 0.00290

Gnomad4 AMR exome AF: 0.00783

Gnomad4 ASJ exome AF: 0.00777

Gnomad4 EAS exome AF: 0.0141

Gnomad4 SAS exome AF: 0.0169

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.0185

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0122 AC: 1866 AN: 152334 Hom.: 14 Cov.: 32 AF XY: 0.0120 AC XY: 895 AN XY: 74488

Gnomad4 AFR AF: 0.00423

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.0125

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.00960

Gnomad4 NFE AF: 0.0178

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0154 Hom.: 5

Bravo AF: 0.0113

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0187 AC: 72

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0169 AC: 145

ExAC AF: 0.0138 AC: 1672

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.0158

EpiControl AF: 0.0154

ClinVar

Significance: Benign/Likely 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	Invitae	Jan 20, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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)	Feb 10, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

PYGL: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Benign	0.014	T;T
MetaSVM	Uncertain	0.59	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.63
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.034	D;D
Polyphen		0.0060	.;B
Vest4		0.35
MutPred		0.29		.;Gain of catalytic residue at I806 (P = 0.0913);
MPC		0.16
ClinPred		0.077	T
GERP RS		6.1
Varity_R		0.85
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs34313873; hg19: chr14-51372238; COSMIC: COSV99046576; COSMIC: COSV99046576;