NM_002863.5:c.2016C>T

Variant names:

• chr14-50910056-G-A
• rs15669
• NM_002863.5:c.2016C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002863.5(PYGL):​c.2016C>T​(p.Thr672Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,613,832 control chromosomes in the GnomAD database, including 19,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4367 hom., cov: 33)
  • Exomes 𝑓: 0.13 (15028 hom.)
• Consequence: PYGL NM_002863.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.01
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• glycogen storage disease VI

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 14-50910056-G-A is Benign according to our data. Variant chr14-50910056-G-A is described in ClinVar as Benign. ClinVar VariationId is 258836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002863.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGL	NM_002863.5	MANE Select	c.2016C>T	p.Thr672Thr	synonymous	Exon 17 of 20	NP_002854.3
	PYGL	NM_001163940.2		c.1914C>T	p.Thr638Thr	synonymous	Exon 16 of 19	NP_001157412.1	P06737-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGL	ENST00000216392.8	TSL:1 MANE Select	c.2016C>T	p.Thr672Thr	synonymous	Exon 17 of 20	ENSP00000216392.7	P06737-1
	PYGL	ENST00000532462.5	TSL:1	c.2016C>T	p.Thr672Thr	synonymous	Exon 17 of 20	ENSP00000431657.1	E9PK47
	PYGL	ENST00000874287.1		c.2031C>T	p.Thr677Thr	synonymous	Exon 17 of 20	ENSP00000544346.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31199 AN: 152002 Hom.: 4362 Cov.: 33

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.149 AC: 37481 AN: 251450 AF XY: 0.148

Gnomad AFR exome AF: 0.409

Gnomad AMR exome AF: 0.0872

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.107

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.134 AC: 195900 AN: 1461712 Hom.: 15028 Cov.: 33 AF XY: 0.136 AC XY: 98607 AN XY: 727162

African (AFR) AF: 0.415 AC: 13906 AN: 33470

American (AMR) AF: 0.0939 AC: 4200 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3584 AN: 26134

East Asian (EAS) AF: 0.148 AC: 5865 AN: 39698

South Asian (SAS) AF: 0.189 AC: 16268 AN: 86244

European-Finnish (FIN) AF: 0.127 AC: 6800 AN: 53420

Middle Eastern (MID) AF: 0.156 AC: 901 AN: 5768

European-Non Finnish (NFE) AF: 0.122 AC: 135809 AN: 1111868

Other (OTH) AF: 0.142 AC: 8567 AN: 60386

GnomAD4 genome AF: 0.205 AC: 31229 AN: 152120 Hom.: 4367 Cov.: 33 AF XY: 0.204 AC XY: 15137 AN XY: 74372

African (AFR) AF: 0.407 AC: 16862 AN: 41466

American (AMR) AF: 0.132 AC: 2023 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 456 AN: 3468

East Asian (EAS) AF: 0.108 AC: 560 AN: 5180

South Asian (SAS) AF: 0.172 AC: 827 AN: 4820

European-Finnish (FIN) AF: 0.130 AC: 1373 AN: 10586

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8615 AN: 68000

Other (OTH) AF: 0.167 AC: 353 AN: 2114

Alfa AF: 0.156 Hom.: 8543

Bravo AF: 0.209

Asia WGS AF: 0.159 AC: 552 AN: 3478

EpiCase AF: 0.123

EpiControl AF: 0.129

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycogen storage disease, type VI (3)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.0080
DANN	Benign	0.82
PhyloP100		-4.0
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs15669; hg19: chr14-51376774; COSMIC: COSV53584806; COSMIC: COSV53584806;