rs34313873

Variant names:

• chr14-50905520-T-A
• rs34313873
• NM_002863.5:c.2416A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002863.5(PYGL):​c.2416A>T​(p.Ile806Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,614,030 control chromosomes in the GnomAD database, including 274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (14 hom., cov: 32)
  • Exomes 𝑓: 0.017 (260 hom.)
• Consequence: PYGL NM_002863.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 8.02
• 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014384419).
• BP6: Variant 14-50905520-T-A is Benign according to our data. Variant chr14-50905520-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0122 (1866/152334) while in subpopulation NFE AF = 0.0178 (1208/68026). AF 95% confidence interval is 0.0169. There are 14 homozygotes in GnomAd4. There are 895 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

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.2416A>T	p.Ile806Leu	missense	Exon 20 of 20	NP_002854.3
	PYGL	NM_001163940.2		c.2314A>T	p.Ile772Leu	missense	Exon 19 of 19	NP_001157412.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGL	ENST00000216392.8	TSL:1 MANE Select	c.2416A>T	p.Ile806Leu	missense	Exon 20 of 20	ENSP00000216392.7
	PYGL	ENST00000532462.5	TSL:1	c.2379+2751A>T		intron	N/A	ENSP00000431657.1
	PYGL	ENST00000874287.1		c.2431A>T	p.Ile811Leu	missense	Exon 20 of 20	ENSP00000544346.1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1868 AN: 152216 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.00960

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0178

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.0133 AC: 3351 AN: 251450 AF XY: 0.0138

Gnomad AFR exome AF: 0.00326

Gnomad AMR exome AF: 0.00752

Gnomad ASJ exome AF: 0.00744

Gnomad EAS exome AF: 0.0106

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0171 AC: 24955 AN: 1461696 Hom.: 260 Cov.: 33 AF XY: 0.0171 AC XY: 12468 AN XY: 727150

African (AFR) AF: 0.00290 AC: 97 AN: 33474

American (AMR) AF: 0.00783 AC: 350 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00777 AC: 203 AN: 26124

East Asian (EAS) AF: 0.0141 AC: 561 AN: 39688

South Asian (SAS) AF: 0.0169 AC: 1457 AN: 86254

European-Finnish (FIN) AF: 0.0122 AC: 651 AN: 53416

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.0185 AC: 20519 AN: 1111860

Other (OTH) AF: 0.0178 AC: 1072 AN: 60390

GnomAD4 genome AF: 0.0122 AC: 1866 AN: 152334 Hom.: 14 Cov.: 32 AF XY: 0.0120 AC XY: 895 AN XY: 74488

African (AFR) AF: 0.00423 AC: 176 AN: 41576

American (AMR) AF: 0.0121 AC: 185 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.0125 AC: 65 AN: 5184

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4824

European-Finnish (FIN) AF: 0.00960 AC: 102 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0178 AC: 1208 AN: 68026

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.0154 Hom.: 5

Bravo AF: 0.0113

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0187 AC: 72

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0169 AC: 145

ExAC AF: 0.0138 AC: 1672

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.0158

EpiControl AF: 0.0154

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		8.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.034	D
Polyphen		0.0060	B
Vest4		0.35
MutPred		0.29		Gain of catalytic residue at I806 (P = 0.0913)
MPC		0.16
ClinPred		0.077	T
GERP RS		6.1
Varity_R		0.85
gMVP		0.82
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs34313873; hg19: chr14-51372238; COSMIC: COSV99046576; COSMIC: COSV99046576;