14-50905597-C-T

Variant names:

• chr14-50905597-C-T
• rs2275466
• NM_002863.5:c.2380-41G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002863.5(PYGL):​c.2380-41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0243 in 1,595,938 control chromosomes in the GnomAD database, including 695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (91 hom., cov: 33)
  • Exomes 𝑓: 0.024 (604 hom.)
• Consequence: PYGL NM_002863.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.137
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 14-50905597-C-T is Benign according to our data. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50905597-C-T is described in CliVar as Benign. Clinvar id is 258839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGL	NM_002863.5	c.2380-41G>A		intron_variant	Intron 19 of 19	ENST00000216392.8	NP_002854.3
PYGL	NM_001163940.2	c.2278-41G>A		intron_variant	Intron 18 of 18		NP_001157412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGL	ENST00000216392.8	c.2380-41G>A		intron_variant	Intron 19 of 19	1	NM_002863.5	ENSP00000216392.7
PYGL	ENST00000532462.5	c.2379+2674G>A		intron_variant	Intron 19 of 19	1		ENSP00000431657.1
PYGL	ENST00000544180.6	c.2278-41G>A		intron_variant	Intron 18 of 18	2		ENSP00000443787.1

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 4677 AN: 152130 Hom.: 90 Cov.: 33

Gnomad AFR AF: 0.0442

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0498

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.0642

Gnomad SAS AF: 0.0330

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0309 AC: 7749 AN: 250550 AF XY: 0.0296

Gnomad AFR exome AF: 0.0456

Gnomad AMR exome AF: 0.0582

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.0620

Gnomad FIN exome AF: 0.0242

Gnomad NFE exome AF: 0.0177

Gnomad OTH exome AF: 0.0265

GnomAD4 exome AF: 0.0237 AC: 34159 AN: 1443690 Hom.: 604 Cov.: 29 AF XY: 0.0237 AC XY: 17063 AN XY: 719568

African (AFR) AF: 0.0447 AC: 1475 AN: 33020

American (AMR) AF: 0.0584 AC: 2610 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 374 AN: 26014

East Asian (EAS) AF: 0.0774 AC: 3063 AN: 39574

South Asian (SAS) AF: 0.0338 AC: 2903 AN: 85862

European-Finnish (FIN) AF: 0.0247 AC: 1319 AN: 53360

Middle Eastern (MID) AF: 0.0129 AC: 74 AN: 5734

European-Non Finnish (NFE) AF: 0.0189 AC: 20737 AN: 1095668

Other (OTH) AF: 0.0268 AC: 1604 AN: 59762

GnomAD4 genome AF: 0.0308 AC: 4686 AN: 152248 Hom.: 91 Cov.: 33 AF XY: 0.0321 AC XY: 2393 AN XY: 74440

African (AFR) AF: 0.0443 AC: 1839 AN: 41520

American (AMR) AF: 0.0497 AC: 760 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3472

East Asian (EAS) AF: 0.0641 AC: 333 AN: 5192

South Asian (SAS) AF: 0.0332 AC: 160 AN: 4820

European-Finnish (FIN) AF: 0.0209 AC: 222 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0186 AC: 1266 AN: 68020

Other (OTH) AF: 0.0279 AC: 59 AN: 2114

Alfa AF: 0.0211 Hom.: 49

Bravo AF: 0.0334

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.2
DANN	Benign	0.37
PhyloP100		0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2275466; hg19: chr14-51372315; COSMIC: COSV53586255; COSMIC: COSV53586255;