rs2075643

Variant names:

• chr14-50916714-G-A
• rs2075643
• NM_002863.5:c.1020C>T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_002863.5(PYGL):​c.1020C>T​(p.Asp340Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.192 in 1,612,936 control chromosomes in the GnomAD database, including 34,590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2974 hom., cov: 33)
  • Exomes 𝑓: 0.19 (31616 hom.)
• Consequence: PYGL NM_002863.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.97

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 14-50916714-G-A is Benign according to our data. Variant chr14-50916714-G-A is described in ClinVar as [Benign]. Clinvar id is 258830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50916714-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGL	NM_002863.5	c.1020C>T	p.Asp340Asp	synonymous_variant	Exon 9 of 20	ENST00000216392.8	NP_002854.3
PYGL	NM_001163940.2	c.918C>T	p.Asp306Asp	synonymous_variant	Exon 8 of 19		NP_001157412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGL	ENST00000216392.8	c.1020C>T	p.Asp340Asp	synonymous_variant	Exon 9 of 20	1	NM_002863.5	ENSP00000216392.7
PYGL	ENST00000532462.5	c.1020C>T	p.Asp340Asp	synonymous_variant	Exon 9 of 20	1		ENSP00000431657.1
PYGL	ENST00000544180.6	c.918C>T	p.Asp306Asp	synonymous_variant	Exon 8 of 19	2		ENSP00000443787.1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26238 AN: 152098 Hom.: 2968 Cov.: 33

Gnomad AFR AF: 0.0646

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.202

GnomAD3 exomes AF: 0.239 AC: 60106 AN: 251412 Hom.: 9323 AF XY: 0.230 AC XY: 31266 AN XY: 135878

Gnomad AFR exome AF: 0.0652

Gnomad AMR exome AF: 0.480

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.436

Gnomad SAS exome AF: 0.222

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.195 AC: 284209 AN: 1460720 Hom.: 31616 Cov.: 33 AF XY: 0.194 AC XY: 141273 AN XY: 726756

Gnomad4 AFR exome AF: 0.0638

Gnomad4 AMR exome AF: 0.458

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.424

Gnomad4 SAS exome AF: 0.220

Gnomad4 FIN exome AF: 0.199

Gnomad4 NFE exome AF: 0.177

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.173 AC: 26259 AN: 152216 Hom.: 2974 Cov.: 33 AF XY: 0.178 AC XY: 13272 AN XY: 74434

Gnomad4 AFR AF: 0.0646

Gnomad4 AMR AF: 0.315

Gnomad4 ASJ AF: 0.159

Gnomad4 EAS AF: 0.442

Gnomad4 SAS AF: 0.240

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.204

Alfa AF: 0.185 Hom.: 3714

Bravo AF: 0.183

Asia WGS AF: 0.327 AC: 1136 AN: 3478

EpiCase AF: 0.189

EpiControl AF: 0.187

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Glycogen storage disease, type VI Benign:3

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	9.6
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

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: rs2075643; hg19: chr14-51383432; COSMIC: COSV53583915; COSMIC: COSV53583915;