rs147211684

chr14-50915977-G-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.1093-6C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00855 in 1,613,928 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0087 (142 hom.)
• Consequence: PYGL NM_002863.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002281
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.536

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 14-50915977-G-T is Benign according to our data. Variant chr14-50915977-G-T is described in ClinVar as [Benign]. Clinvar id is 193644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0068 (1036/152320) while in subpopulation SAS AF= 0.0284 (137/4832). AF 95% confidence interval is 0.0245. There are 13 homozygotes in gnomad4. There are 574 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGL	NM_002863.5	c.1093-6C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000216392.8
PYGL	NM_001163940.2	c.991-6C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGL	ENST00000216392.8	c.1093-6C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002863.5	P1
PYGL	ENST00000532462.5	c.1093-6C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
PYGL	ENST00000544180.6	c.991-6C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2
PYGL	ENST00000528757.2			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00679 AC: 1034 AN: 152202 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0279

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00815

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.0109 AC: 2730 AN: 250962 Hom.: 46 AF XY: 0.0121 AC XY: 1648 AN XY: 135664

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.0361

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0299

Gnomad FIN exome AF: 0.00954

Gnomad NFE exome AF: 0.00943

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00874 AC: 12770 AN: 1461608 Hom.: 142 Cov.: 32 AF XY: 0.00962 AC XY: 6992 AN XY: 727086

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.0357

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0305

Gnomad4 FIN exome AF: 0.0106

Gnomad4 NFE exome AF: 0.00710

Gnomad4 OTH exome AF: 0.00878

GnomAD4 genome AF: 0.00680 AC: 1036 AN: 152320 Hom.: 13 Cov.: 33 AF XY: 0.00771 AC XY: 574 AN XY: 74474

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.0357

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0284

Gnomad4 FIN AF: 0.0113

Gnomad4 NFE AF: 0.00815

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00969 Hom.: 8

Bravo AF: 0.00507

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.00938

EpiControl AF: 0.00812

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type VI Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 11, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 21, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	8.5
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0023
dbscSNV1_RF	Benign	0.11
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: rs147211684; hg19: chr14-51382695;