rs147211684

Positions:

chr14-50915977-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002863.5(PYGL):c.1093-6C>A variant causes a splice region, 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, intron

Scores

Splicing: ADA: 0.002281

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.536

Variant links:

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 links:

PYGL (HGNC:):

PYGL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGL	NM_002863.5 linkuse as main transcript	c.1093-6C>A		splice_region_variant, intron_variant		ENST00000216392.8	NP_002854.3	P06737-1
PYGL	NM_001163940.2 linkuse as main transcript	c.991-6C>A		splice_region_variant, intron_variant			NP_001157412.1	P06737-2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
PYGL	ENST00000216392.8 linkuse as main transcript	c.1093-6C>A	splice_region_variant, intron_variant	1	NM_002863.5	ENSP00000216392.7	P06737-1
PYGL	ENST00000532462.5 linkuse as main transcript	c.1093-6C>A	splice_region_variant, intron_variant	1		ENSP00000431657.1	E9PK47
PYGL	ENST00000544180.6 linkuse as main transcript	c.991-6C>A	splice_region_variant, intron_variant	2		ENSP00000443787.1	P06737-2
PYGL	ENST00000528757.2 linkuse as main transcript	n.-37C>A	upstream_gene_variant	3

Frequencies

GnomAD3 genomes

AF:

0.00679

AC:

1034

AN:

152202

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0121

AC XY:

1648

AN XY:

135664

show subpopulations

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.:

AF XY:

0.00962

AC XY:

6992

AN XY:

727086

show subpopulations

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.:

Cov.:

AF XY:

0.00771

AC XY:

574

AN XY:

74474

show subpopulations

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.:

Bravo

AF:

0.00507

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.00938

EpiControl

AF:

0.00812

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Labcorp Genetics (formerly Invitae), Labcorp	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	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over