chr14-50905402-T-C

Position:

chr14-50905402-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002863.5(PYGL):c.2534A>G(p.Asn845Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,612,492 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 68 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 72 hom. )

Consequence

PYGL
NM_002863.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.353

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=0.0017891526).

BP6

Variant 14-50905402-T-C is Benign according to our data. Variant chr14-50905402-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 258843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905402-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGL	NM_002863.5 linkuse as main transcript	c.2534A>G	p.Asn845Ser	missense_variant	20/20	ENST00000216392.8	NP_002854.3	P06737-1
PYGL	NM_001163940.2 linkuse as main transcript	c.2432A>G	p.Asn811Ser	missense_variant	19/19		NP_001157412.1	P06737-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PYGL	ENST00000216392.8 linkuse as main transcript	c.2534A>G	p.Asn845Ser	missense_variant	20/20	1	NM_002863.5	ENSP00000216392.7	P06737-1
PYGL	ENST00000532462.5 linkuse as main transcript	c.2379+2869A>G		intron_variant		1		ENSP00000431657.1	E9PK47
PYGL	ENST00000544180.6 linkuse as main transcript	c.2432A>G	p.Asn811Ser	missense_variant	19/19	2		ENSP00000443787.1	P06737-2

Frequencies

GnomAD3 genomes

AF:

0.0161

AC:

2444

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0557

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.00397

AC:

998

AN:

251346

Hom.:

AF XY:

0.00294

AC XY:

399

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.0535

Gnomad AMR exome

AF:

0.00257

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00175

AC:

2560

AN:

1460170

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

1123

AN XY:

726518

show subpopulations

Gnomad4 AFR exome

AF:

0.0591

Gnomad4 AMR exome

AF:

0.00268

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000328

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000124

Gnomad4 OTH exome

AF:

0.00446

GnomAD4 genome

AF:

0.0161

AC:

2452

AN:

152322

Hom.:

Cov.:

AF XY:

0.0151

AC XY:

1128

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0557

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.00272

Hom.:

Bravo

AF:

0.0178

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0502

AC:

221

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00489

AC:

594

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

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 23, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 08, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 24, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.11

.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.57

T;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.20

.;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.11

N;N

REVEL

Benign

0.20

Sift

Benign

0.14

T;T

Sift4G

Benign

0.71

T;T

Polyphen

0.0

.;B

Vest4

0.090

MVP

0.72

MPC

0.085

ClinPred

0.0012

GERP RS

2.4

Varity_R

0.018

gMVP

0.35

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

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