14-50905385-C-G

Variant names:

• chr14-50905385-C-G
• rs1042266
• NM_002863.5:c.*7G>C

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.*7G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,604,808 control chromosomes in the GnomAD database, including 39,393 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3313 hom., cov: 32)
  • Exomes 𝑓: 0.21 (36080 hom.)
• Consequence: PYGL NM_002863.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.312
• Publications: 13 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 (BayesDel_noAF=-0.83).
• BP6: Variant 14-50905385-C-G is Benign according to our data. Variant chr14-50905385-C-G is described in ClinVar as Benign. ClinVar VariationId is 258829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGL	NM_002863.5	c.*7G>C		3_prime_UTR_variant	Exon 20 of 20	ENST00000216392.8	NP_002854.3
PYGL	NM_001163940.2	c.*7G>C		3_prime_UTR_variant	Exon 19 of 19		NP_001157412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGL	ENST00000216392.8	c.*7G>C		3_prime_UTR_variant	Exon 20 of 20	1	NM_002863.5	ENSP00000216392.7
PYGL	ENST00000532462.5	c.2379+2886G>C		intron_variant	Intron 19 of 19	1		ENSP00000431657.1
PYGL	ENST00000544180.6	c.*7G>C		3_prime_UTR_variant	Exon 19 of 19	2		ENSP00000443787.1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28149 AN: 151886 Hom.: 3306 Cov.: 32

Gnomad AFR AF: 0.0703

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.458

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.227

GnomAD2 exomes AF: 0.251 AC: 63101 AN: 251172 AF XY: 0.242

Gnomad AFR exome AF: 0.0678

Gnomad AMR exome AF: 0.502

Gnomad ASJ exome AF: 0.185

Gnomad EAS exome AF: 0.446

Gnomad FIN exome AF: 0.208

Gnomad NFE exome AF: 0.191

Gnomad OTH exome AF: 0.240

GnomAD4 exome AF: 0.209 AC: 303623 AN: 1452804 Hom.: 36080 Cov.: 32 AF XY: 0.209 AC XY: 150881 AN XY: 723342

African (AFR) AF: 0.0670 AC: 2229 AN: 33292

American (AMR) AF: 0.481 AC: 21472 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 5025 AN: 26064

East Asian (EAS) AF: 0.447 AC: 17727 AN: 39624

South Asian (SAS) AF: 0.225 AC: 19357 AN: 86036

European-Finnish (FIN) AF: 0.205 AC: 10966 AN: 53382

Middle Eastern (MID) AF: 0.274 AC: 1570 AN: 5740

European-Non Finnish (NFE) AF: 0.192 AC: 212042 AN: 1103926

Other (OTH) AF: 0.220 AC: 13235 AN: 60068

GnomAD4 genome AF: 0.185 AC: 28166 AN: 152004 Hom.: 3313 Cov.: 32 AF XY: 0.190 AC XY: 14124 AN XY: 74298

African (AFR) AF: 0.0702 AC: 2913 AN: 41484

American (AMR) AF: 0.335 AC: 5121 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 640 AN: 3468

East Asian (EAS) AF: 0.458 AC: 2362 AN: 5160

South Asian (SAS) AF: 0.247 AC: 1190 AN: 4816

European-Finnish (FIN) AF: 0.207 AC: 2186 AN: 10536

Middle Eastern (MID) AF: 0.286 AC: 83 AN: 290

European-Non Finnish (NFE) AF: 0.193 AC: 13092 AN: 67958

Other (OTH) AF: 0.229 AC: 484 AN: 2116

Alfa AF: 0.130 Hom.: 317

Bravo AF: 0.198

Asia WGS AF: 0.328 AC: 1141 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

- -

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disease, type VI Benign:2

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. -

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	-0.83
CADD	Benign	4.0
DANN	Benign	0.60
PhyloP100		0.31
Mutation Taster		=100/0	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: rs1042266; hg19: chr14-51372103;