14-50911892-C-T

Position:

• chr14-50911892-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002863.5(PYGL):​c.1828-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,614,016 control chromosomes in the GnomAD database, including 445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (25 hom., cov: 32)
  • Exomes 𝑓: 0.022 (420 hom.)
• Consequence: PYGL NM_002863.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.908

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 14-50911892-C-T is Benign according to our data. Variant chr14-50911892-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0143 (2170/152248) while in subpopulation NFE AF= 0.0229 (1556/68024). AF 95% confidence interval is 0.0219. There are 25 homozygotes in gnomad4. There are 992 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGL	NM_002863.5	c.1828-21G>A		intron_variant		ENST00000216392.8	NP_002854.3
PYGL	NM_001163940.2	c.1726-21G>A		intron_variant			NP_001157412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGL	ENST00000216392.8	c.1828-21G>A		intron_variant		1	NM_002863.5	ENSP00000216392.7
PYGL	ENST00000532462.5	c.1828-21G>A		intron_variant		1		ENSP00000431657.1
PYGL	ENST00000544180.6	c.1726-21G>A		intron_variant		2		ENSP00000443787.1
PYGL	ENST00000532107.2	n.-21G>A		upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2171 AN: 152130 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00512

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.00952

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0162

GnomAD3 exomes AF: 0.0139 AC: 3490 AN: 251460 Hom.: 40 AF XY: 0.0138 AC XY: 1870 AN XY: 135902

Gnomad AFR exome AF: 0.00529

Gnomad AMR exome AF: 0.0100

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00738

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0217 AC: 31756 AN: 1461768 Hom.: 420 Cov.: 34 AF XY: 0.0212 AC XY: 15437 AN XY: 727180

Gnomad4 AFR exome AF: 0.00397

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.00337

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00732

Gnomad4 FIN exome AF: 0.0108

Gnomad4 NFE exome AF: 0.0257

Gnomad4 OTH exome AF: 0.0209

GnomAD4 genome AF: 0.0143 AC: 2170 AN: 152248 Hom.: 25 Cov.: 32 AF XY: 0.0133 AC XY: 992 AN XY: 74440

Gnomad4 AFR AF: 0.00513

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.00952

Gnomad4 NFE AF: 0.0229

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0132 Hom.: 13

Bravo AF: 0.0147

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2021	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 17, 2017	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.35
DANN	Benign	0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs75220125; hg19: chr14-51378610;