rs946616

Variant names:

• chr14-50921064-C-T
• rs946616
• NM_002863.5:c.664G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002863.5(PYGL):​c.664G>A​(p.Val222Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0679 in 1,610,242 control chromosomes in the GnomAD database, including 4,607 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (925 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3682 hom.)
• Consequence: PYGL NM_002863.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.12
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017901957).
• BP6: Variant 14-50921064-C-T is Benign according to our data. Variant chr14-50921064-C-T is described in ClinVar as Benign. ClinVar VariationId is 258846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 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.664G>A	p.Val222Ile	missense	Exon 6 of 20	NP_002854.3
	PYGL	NM_001163940.2		c.562G>A	p.Val188Ile	missense	Exon 5 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.664G>A	p.Val222Ile	missense	Exon 6 of 20	ENSP00000216392.7	P06737-1
	PYGL	ENST00000532462.5	TSL:1	c.664G>A	p.Val222Ile	missense	Exon 6 of 20	ENSP00000431657.1	E9PK47
	PYGL	ENST00000874287.1		c.679G>A	p.Val227Ile	missense	Exon 6 of 20	ENSP00000544346.1

Frequencies

GnomAD3 genomes AF: 0.0950 AC: 14451 AN: 152086 Hom.: 924 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0484

Gnomad ASJ AF: 0.0866

Gnomad EAS AF: 0.0164

Gnomad SAS AF: 0.0865

Gnomad FIN AF: 0.0546

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0649

Gnomad OTH AF: 0.0786

GnomAD2 exomes AF: 0.0694 AC: 17431 AN: 251334 AF XY: 0.0693

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.0315

Gnomad ASJ exome AF: 0.0942

Gnomad EAS exome AF: 0.00745

Gnomad FIN exome AF: 0.0532

Gnomad NFE exome AF: 0.0685

Gnomad OTH exome AF: 0.0697

GnomAD4 exome AF: 0.0651 AC: 94945 AN: 1458038 Hom.: 3682 Cov.: 30 AF XY: 0.0662 AC XY: 48018 AN XY: 725638

African (AFR) AF: 0.185 AC: 6184 AN: 33348

American (AMR) AF: 0.0342 AC: 1530 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0903 AC: 2358 AN: 26110

East Asian (EAS) AF: 0.0357 AC: 1415 AN: 39686

South Asian (SAS) AF: 0.0931 AC: 8019 AN: 86166

European-Finnish (FIN) AF: 0.0566 AC: 3025 AN: 53414

Middle Eastern (MID) AF: 0.0693 AC: 398 AN: 5746

European-Non Finnish (NFE) AF: 0.0614 AC: 68054 AN: 1108594

Other (OTH) AF: 0.0657 AC: 3962 AN: 60260

GnomAD4 genome AF: 0.0950 AC: 14463 AN: 152204 Hom.: 925 Cov.: 32 AF XY: 0.0929 AC XY: 6916 AN XY: 74406

African (AFR) AF: 0.184 AC: 7651 AN: 41498

American (AMR) AF: 0.0483 AC: 739 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0866 AC: 300 AN: 3466

East Asian (EAS) AF: 0.0164 AC: 85 AN: 5178

South Asian (SAS) AF: 0.0865 AC: 418 AN: 4830

European-Finnish (FIN) AF: 0.0546 AC: 579 AN: 10614

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0649 AC: 4412 AN: 68010

Other (OTH) AF: 0.0773 AC: 163 AN: 2108

Alfa AF: 0.0740 Hom.: 2143

Bravo AF: 0.0966

TwinsUK AF: 0.0566 AC: 210

ALSPAC AF: 0.0545 AC: 210

ESP6500AA AF: 0.183 AC: 807

ESP6500EA AF: 0.0649 AC: 558

ExAC AF: 0.0759 AC: 9219

Asia WGS AF: 0.0530 AC: 183 AN: 3478

EpiCase AF: 0.0653

EpiControl AF: 0.0694

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Glycogen storage disease, type VI (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.38
Sift	Benign	0.11	T
Sift4G	Benign	0.25	T
Polyphen		0.016	B
Vest4		0.066
MPC		0.097
ClinPred		0.025	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.57
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs946616; hg19: chr14-51387782;