rs78558135

chr14-50905402-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.353

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=0.0017891526).
• 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	UniProt
PYGL	NM_002863.5	c.2534A>G	p.Asn845Ser	missense_variant	20/20	ENST00000216392.8
PYGL	NM_001163940.2	c.2432A>G	p.Asn811Ser	missense_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGL	ENST00000216392.8	c.2534A>G	p.Asn845Ser	missense_variant	20/20	1	NM_002863.5	P1
PYGL	ENST00000532462.5	c.2379+2869A>G		intron_variant		1
PYGL	ENST00000544180.6	c.2432A>G	p.Asn811Ser	missense_variant	19/19	2

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2444 AN: 152204 Hom.: 67 Cov.: 33

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.: 28 AF XY: 0.00294 AC XY: 399 AN XY: 135842

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.: 72 Cov.: 33 AF XY: 0.00155 AC XY: 1123 AN XY: 726518

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.: 68 Cov.: 33 AF XY: 0.0151 AC XY: 1128 AN XY: 74498

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.: 20

Bravo AF: 0.0178

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0502 AC: 221

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00489 AC: 594

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type VI Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 08, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -
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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

May 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	13
Dann	Benign	0.92
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.29	T
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	T
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

Other links and lift over

dbSNP: rs78558135; hg19: chr14-51372120;