rs35501326

chr14-50917033-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3 BP4_Strong BS1 BS2

The NM_002863.5(PYGL):c.928C>T(p.Arg310Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,613,808 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (14 hom.)
• Consequence: PYGL NM_002863.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.08

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 -11 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.015972316).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00701 (1068/152258) while in subpopulation AFR AF= 0.0238 (990/41534). AF 95% confidence interval is 0.0226. There are 16 homozygotes in gnomad4. There are 487 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGL	NM_002863.5	c.928C>T	p.Arg310Cys	missense_variant	8/20	ENST00000216392.8
PYGL	NM_001163940.2	c.826C>T	p.Arg276Cys	missense_variant	7/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGL	ENST00000216392.8	c.928C>T	p.Arg310Cys	missense_variant	8/20	1	NM_002863.5	P1
PYGL	ENST00000532462.5	c.928C>T	p.Arg310Cys	missense_variant	8/20	1
PYGL	ENST00000544180.6	c.826C>T	p.Arg276Cys	missense_variant	7/19	2
PYGL	ENST00000553872.1	n.729C>T		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes AF: 0.00699 AC: 1064 AN: 152140 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0238

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00175 AC: 441 AN: 251478 Hom.: 6 AF XY: 0.00125 AC XY: 170 AN XY: 135914

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000770 AC: 1125 AN: 1461550 Hom.: 14 Cov.: 32 AF XY: 0.000685 AC XY: 498 AN XY: 727136

Gnomad4 AFR exome AF: 0.0242

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00701 AC: 1068 AN: 152258 Hom.: 16 Cov.: 33 AF XY: 0.00654 AC XY: 487 AN XY: 74448

Gnomad4 AFR AF: 0.0238

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00134 Hom.: 5

Bravo AF: 0.00786

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0225 AC: 99

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00221 AC: 268

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type VI Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -

not provided Benign:1

Likely 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	Uncertain	0.49
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Uncertain	0.74	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-7.1	D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.41	B;.;D
Vest4		0.80
MVP		1.0
MPC		0.63
ClinPred		0.14	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.87

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: rs35501326; hg19: chr14-51383751;