NM_002863.5:c.244-34G>A

Variant names:

• chr14-50937871-C-T
• rs17123214
• NM_002863.5:c.244-34G>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.244-34G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 1,552,696 control chromosomes in the GnomAD database, including 339 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (31 hom., cov: 33)
  • Exomes 𝑓: 0.019 (308 hom.)
• Consequence: PYGL NM_002863.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.148
• Publications: 2 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=-0.85).
• BP6: Variant 14-50937871-C-T is Benign according to our data. Variant chr14-50937871-C-T is described in ClinVar as Benign. ClinVar VariationId is 258842.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 = 0.0221 (3358/152268) while in subpopulation AFR AF = 0.0366 (1519/41540). AF 95% confidence interval is 0.035. There are 31 homozygotes in GnomAd4. There are 1596 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGL	NM_002863.5	MANE Select	c.244-34G>A		intron	N/A	NP_002854.3
	PYGL	NM_001163940.2		c.244-2686G>A		intron	N/A	NP_001157412.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGL	ENST00000216392.8	TSL:1 MANE Select	c.244-34G>A		intron	N/A	ENSP00000216392.7
	PYGL	ENST00000532462.5	TSL:1	c.244-34G>A		intron	N/A	ENSP00000431657.1
	PYGL	ENST00000530336.2	TSL:1	n.311-34G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3354 AN: 152150 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.0173

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.00942

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0166 AC: 4123 AN: 248690 AF XY: 0.0164

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.00757

Gnomad EAS exome AF: 0.0132

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.0174

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0188 AC: 26380 AN: 1400428 Hom.: 308 Cov.: 25 AF XY: 0.0188 AC XY: 13172 AN XY: 700268

African (AFR) AF: 0.0366 AC: 1176 AN: 32156

American (AMR) AF: 0.0116 AC: 518 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00752 AC: 194 AN: 25788

East Asian (EAS) AF: 0.0247 AC: 975 AN: 39400

South Asian (SAS) AF: 0.0174 AC: 1482 AN: 85046

European-Finnish (FIN) AF: 0.0123 AC: 639 AN: 51748

Middle Eastern (MID) AF: 0.0169 AC: 93 AN: 5518

European-Non Finnish (NFE) AF: 0.0190 AC: 20055 AN: 1057752

Other (OTH) AF: 0.0214 AC: 1248 AN: 58402

GnomAD4 genome AF: 0.0221 AC: 3358 AN: 152268 Hom.: 31 Cov.: 33 AF XY: 0.0214 AC XY: 1596 AN XY: 74452

African (AFR) AF: 0.0366 AC: 1519 AN: 41540

American (AMR) AF: 0.0166 AC: 254 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3470

East Asian (EAS) AF: 0.0173 AC: 90 AN: 5188

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4820

European-Finnish (FIN) AF: 0.00942 AC: 100 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0182 AC: 1240 AN: 68020

Other (OTH) AF: 0.0218 AC: 46 AN: 2110

Alfa AF: 0.0205 Hom.: 61

Bravo AF: 0.0226

Asia WGS AF: 0.0170 AC: 58 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.85
DANN	Benign	0.29
PhyloP100		-0.15
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: rs17123214; hg19: chr14-51404589;