rs34313873

Positions:

chr14-50905520-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 8.02

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
PYGL	NM_002863.5 linkuse as main transcript	c.2416A>T	p.Ile806Leu	missense_variant	20/20	ENST00000216392.8	NP_002854.3
PYGL	NM_001163940.2 linkuse as main transcript	c.2314A>T	p.Ile772Leu	missense_variant	19/19		NP_001157412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGL	ENST00000216392.8 linkuse as main transcript	c.2416A>T	p.Ile806Leu	missense_variant	20/20	1	NM_002863.5	ENSP00000216392	P1	P06737-1
PYGL	ENST00000532462.5 linkuse as main transcript	c.2379+2751A>T		intron_variant		1		ENSP00000431657
PYGL	ENST00000544180.6 linkuse as main transcript	c.2314A>T	p.Ile772Leu	missense_variant	19/19	2		ENSP00000443787		P06737-2

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1868

AN:

152216

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0138

AC XY:

1882

AN XY:

135906

show subpopulations

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.:

AF XY:

0.0171

AC XY:

12468

AN XY:

727150

show subpopulations

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.:

Cov.:

AF XY:

0.0120

AC XY:

895

AN XY:

74488

show subpopulations

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.:

Bravo

AF:

0.0113

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0169

AC:

145

ExAC

AF:

0.0138

AC:

1672

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0158

EpiControl

AF:

0.0154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type VI

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

.;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

MetaRNN

Benign

0.014

T;T

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

3.6

.;H

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.63

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over