NM_002863.5:c.2178-27dupT

Variant names:

• chr14-50908981-T-TA
• rs11414268
• NM_002863.5:c.2178-27dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002863.5(PYGL):​c.2178-27dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,531,846 control chromosomes in the GnomAD database, including 72,991 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.35 (10267 hom., cov: 0)
  • Exomes 𝑓: 0.28 (62724 hom.)
• Consequence: PYGL NM_002863.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.780
• Publications: 5 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 -16 ACMG points.

• BP6: Variant 14-50908981-T-TA is Benign according to our data. Variant chr14-50908981-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 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.2178-27dupT		intron	N/A	NP_002854.3
	PYGL	NM_001163940.2		c.2076-27dupT		intron	N/A	NP_001157412.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGL	ENST00000216392.8	TSL:1 MANE Select	c.2178-27_2178-26insT		intron	N/A	ENSP00000216392.7
	PYGL	ENST00000532462.5	TSL:1	c.2178-27_2178-26insT		intron	N/A	ENSP00000431657.1
	PYGL	ENST00000874287.1		c.2193-27_2193-26insT		intron	N/A	ENSP00000544346.1

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53206 AN: 151026 Hom.: 10238 Cov.: 0

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.361

GnomAD2 exomes AF: 0.356 AC: 88857 AN: 249322 AF XY: 0.344

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.573

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.553

Gnomad FIN exome AF: 0.291

Gnomad NFE exome AF: 0.273

Gnomad OTH exome AF: 0.327

GnomAD4 exome AF: 0.284 AC: 392300 AN: 1380708 Hom.: 62724 Cov.: 33 AF XY: 0.285 AC XY: 196783 AN XY: 690496

African (AFR) AF: 0.446 AC: 13782 AN: 30900

American (AMR) AF: 0.553 AC: 24327 AN: 43958

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 6171 AN: 25398

East Asian (EAS) AF: 0.551 AC: 20909 AN: 37930

South Asian (SAS) AF: 0.332 AC: 27986 AN: 84318

European-Finnish (FIN) AF: 0.276 AC: 14163 AN: 51348

Middle Eastern (MID) AF: 0.370 AC: 2070 AN: 5594

European-Non Finnish (NFE) AF: 0.254 AC: 265333 AN: 1044242

Other (OTH) AF: 0.308 AC: 17559 AN: 57020

GnomAD4 genome AF: 0.353 AC: 53277 AN: 151138 Hom.: 10267 Cov.: 0 AF XY: 0.357 AC XY: 26338 AN XY: 73864

African (AFR) AF: 0.453 AC: 18595 AN: 41050

American (AMR) AF: 0.448 AC: 6813 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 841 AN: 3466

East Asian (EAS) AF: 0.555 AC: 2833 AN: 5106

South Asian (SAS) AF: 0.347 AC: 1658 AN: 4774

European-Finnish (FIN) AF: 0.289 AC: 3000 AN: 10368

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18544 AN: 67868

Other (OTH) AF: 0.362 AC: 761 AN: 2104

Alfa AF: 0.204 Hom.: 535

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.78
BranchPoint Hunter		1.0
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: rs11414268; hg19: chr14-51375699;