chr14-50916999-C-T

Variant names:

• chr14-50916999-C-T
• rs116465563
• NM_002863.5:c.962G>A

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.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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R321C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0081 (19 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (17 hom.)
• Consequence: PYGL NM_002863.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.174
• Publications: 4 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=0.003247261).
• BP6: Variant 14-50916999-C-T is Benign according to our data. Variant chr14-50916999-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.962G>A	p.Arg321His	missense	Exon 8 of 20	NP_002854.3
	PYGL	NM_001163940.2		c.860G>A	p.Arg287His	missense	Exon 7 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.962G>A	p.Arg321His	missense	Exon 8 of 20	ENSP00000216392.7	P06737-1
	PYGL	ENST00000532462.5	TSL:1	c.962G>A	p.Arg321His	missense	Exon 8 of 20	ENSP00000431657.1	E9PK47
	PYGL	ENST00000874287.1		c.977G>A	p.Arg326His	missense	Exon 8 of 20	ENSP00000544346.1

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

GnomAD2 exomes AF: 0.00207 AC: 520 AN: 251470 AF XY: 0.00141

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 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

African (AFR) AF: 0.0298 AC: 998 AN: 33476

American (AMR) AF: 0.000850 AC: 38 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111988

Other (OTH) AF: 0.00116 AC: 70 AN: 60394

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

African (AFR) AF: 0.0283 AC: 1177 AN: 41566

American (AMR) AF: 0.00242 AC: 37 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00339 Hom.: 17

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

ClinVar submissions

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.17
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.18
Sift	Benign	0.052	T
Sift4G	Benign	0.17	T
Polyphen		0.050	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
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs116465563; hg19: chr14-51383717; COSMIC: COSV53588186; COSMIC: COSV53588186;