rs116465563

Positions:

• chr14-50916999-C-T

Variant summary

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

The ENST00000216392.8(PYGL):​c.962G>A​(p.Arg321His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,614,200 control chromosomes in the GnomAD database, including 36 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 0.0081 (19 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (17 hom.)
• Consequence: PYGL ENST00000216392.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.174

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=0.003247261).
• BP6: Variant 14-50916999-C-T is Benign according to our data. Variant chr14-50916999-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50916999-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00806 (1228/152340) while in subpopulation AFR AF= 0.0283 (1177/41566). AF 95% confidence interval is 0.027. There are 19 homozygotes in gnomad4. There are 580 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGL	NM_002863.5	c.962G>A	p.Arg321His	missense_variant	8/20	ENST00000216392.8	NP_002854.3
PYGL	NM_001163940.2	c.860G>A	p.Arg287His	missense_variant	7/19		NP_001157412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGL	ENST00000216392.8	c.962G>A	p.Arg321His	missense_variant	8/20	1	NM_002863.5	ENSP00000216392	P1
PYGL	ENST00000532462.5	c.962G>A	p.Arg321His	missense_variant	8/20	1		ENSP00000431657
PYGL	ENST00000544180.6	c.860G>A	p.Arg287His	missense_variant	7/19	2		ENSP00000443787
PYGL	ENST00000553872.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00806 AC: 1227 AN: 152222 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00207 AC: 520 AN: 251470 Hom.: 10 AF XY: 0.00141 AC XY: 191 AN XY: 135914

Gnomad AFR exome AF: 0.0300

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000782 AC: 1143 AN: 1461860 Hom.: 17 Cov.: 32 AF XY: 0.000631 AC XY: 459 AN XY: 727232

Gnomad4 AFR exome AF: 0.0298

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00806 AC: 1228 AN: 152340 Hom.: 19 Cov.: 33 AF XY: 0.00779 AC XY: 580 AN XY: 74496

Gnomad4 AFR AF: 0.0283

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00150 Hom.: 9

Bravo AF: 0.00901

ESP6500AA AF: 0.0311 AC: 137

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00275 AC: 334

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 07, 2022	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2022	See Variant Classification Assertion Criteria. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Uncertain	0.48	.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.40	T;T;T
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.0	.;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.050	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.052	T;T;D
Sift4G	Benign	0.17	T;T;T
Polyphen		0.050	B;.;B
Vest4		0.25
MVP		0.74
MPC		0.14
ClinPred		0.0028	T
GERP RS		0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.27
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs116465563; hg19: chr14-51383717; COSMIC: COSV53588186; COSMIC: COSV53588186;