rs74539788

chr14-50912309-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_002863.5(PYGL):c.1621-6T>C 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 0.00209 in 1,613,774 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (35 hom.)
• Consequence: PYGL NM_002863.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003706
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.32

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-50912309-A-G is Benign according to our data. Variant chr14-50912309-A-G is described in ClinVar as [Benign]. Clinvar id is 258834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0113 (1721/152322) while in subpopulation AFR AF= 0.0391 (1627/41568). AF 95% confidence interval is 0.0376. There are 29 homozygotes in gnomad4. There are 803 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGL	NM_002863.5	c.1621-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000216392.8
PYGL	NM_001163940.2	c.1519-6T>C		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.1621-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002863.5	P1
PYGL	ENST00000532462.5	c.1621-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
	ENST00000557343.1	n.84A>G		non_coding_transcript_exon_variant	1/2	3
PYGL	ENST00000544180.6	c.1519-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1715 AN: 152204 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0391

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00300 AC: 754 AN: 251182 Hom.: 12 AF XY: 0.00225 AC XY: 305 AN XY: 135766

Gnomad AFR exome AF: 0.0408

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00113 AC: 1658 AN: 1461452 Hom.: 35 Cov.: 34 AF XY: 0.000967 AC XY: 703 AN XY: 727064

Gnomad4 AFR exome AF: 0.0393

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000890

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.0113 AC: 1721 AN: 152322 Hom.: 29 Cov.: 32 AF XY: 0.0108 AC XY: 803 AN XY: 74488

Gnomad4 AFR AF: 0.0391

Gnomad4 AMR AF: 0.00411

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00549 Hom.: 10

Bravo AF: 0.0131

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type VI Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not specified Benign:1

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	-0.46
Cadd	Benign	16
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00037
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 31

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs74539788; hg19: chr14-51379027;