rs137880110

Variant names:

• chr14-50909861-A-G
• rs137880110
• NM_002863.5:c.2177+34T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002863.5(PYGL):​c.2177+34T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,609,870 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (85 hom.)
• Consequence: PYGL NM_002863.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.337
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 14-50909861-A-G is Benign according to our data. Variant chr14-50909861-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 258837.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00219 (333/152328) while in subpopulation EAS AF = 0.039 (202/5178). AF 95% confidence interval is 0.0346. There are 8 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.2177+34T>C		intron	N/A	NP_002854.3
	PYGL	NM_001163940.2		c.2075+34T>C		intron	N/A	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.2177+34T>C		intron	N/A	ENSP00000216392.7	P06737-1
	PYGL	ENST00000532462.5	TSL:1	c.2177+34T>C		intron	N/A	ENSP00000431657.1	E9PK47
	PYGL	ENST00000874287.1		c.2192+34T>C		intron	N/A	ENSP00000544346.1

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 334 AN: 152210 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0391

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00476 AC: 1196 AN: 251322 AF XY: 0.00498

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0393

Gnomad FIN exome AF: 0.00527

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00239 AC: 3486 AN: 1457542 Hom.: 85 Cov.: 31 AF XY: 0.00266 AC XY: 1928 AN XY: 725432

African (AFR) AF: 0.0000598 AC: 2 AN: 33418

American (AMR) AF: 0.0000894 AC: 4 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.0497 AC: 1972 AN: 39680

South Asian (SAS) AF: 0.0112 AC: 968 AN: 86146

European-Finnish (FIN) AF: 0.00491 AC: 262 AN: 53400

Middle Eastern (MID) AF: 0.00142 AC: 8 AN: 5620

European-Non Finnish (NFE) AF: 0.000112 AC: 124 AN: 1108214

Other (OTH) AF: 0.00242 AC: 146 AN: 60232

GnomAD4 genome AF: 0.00219 AC: 333 AN: 152328 Hom.: 8 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74480

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.000327 AC: 5 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0390 AC: 202 AN: 5178

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4824

European-Finnish (FIN) AF: 0.00499 AC: 53 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000423 Hom.: 0

Bravo AF: 0.00170

Asia WGS AF: 0.0190 AC: 65 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.57
DANN	Benign	0.28
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism

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: rs137880110; hg19: chr14-51376579;