chr14-50908981-T-TA

Position:

• chr14-50908981-T-TA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002863.5(PYGL):​c.2178-27_2178-26insT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,531,846 control chromosomes in the GnomAD database, including 72,991 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.35 (10267 hom., cov: 0)
  • Exomes 𝑓: 0.28 (62724 hom.)
• Consequence: PYGL NM_002863.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.780

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 -16 ACMG points.

• BP6: Variant 14-50908981-T-TA is Benign according to our data. Variant chr14-50908981-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 258838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGL	NM_002863.5	c.2178-27_2178-26insT		intron_variant		ENST00000216392.8
PYGL	NM_001163940.2	c.2076-27_2076-26insT		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGL	ENST00000216392.8	c.2178-27_2178-26insT		intron_variant		1	NM_002863.5	P1
PYGL	ENST00000532462.5	c.2178-27_2178-26insT		intron_variant		1
PYGL	ENST00000544180.6	c.2076-27_2076-26insT		intron_variant		2
PYGL	ENST00000532107.2	n.351-27_351-26insT		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53206 AN: 151026 Hom.: 10238 Cov.: 0

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.361

GnomAD3 exomes AF: 0.356 AC: 88857 AN: 249322 Hom.: 17876 AF XY: 0.344 AC XY: 46461 AN XY: 135044

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.573

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.553

Gnomad SAS exome AF: 0.343

Gnomad FIN exome AF: 0.291

Gnomad NFE exome AF: 0.273

Gnomad OTH exome AF: 0.327

GnomAD4 exome AF: 0.284 AC: 392300 AN: 1380708 Hom.: 62724 Cov.: 33 AF XY: 0.285 AC XY: 196783 AN XY: 690496

Gnomad4 AFR exome AF: 0.446

Gnomad4 AMR exome AF: 0.553

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.551

Gnomad4 SAS exome AF: 0.332

Gnomad4 FIN exome AF: 0.276

Gnomad4 NFE exome AF: 0.254

Gnomad4 OTH exome AF: 0.308

GnomAD4 genome AF: 0.353 AC: 53277 AN: 151138 Hom.: 10267 Cov.: 0 AF XY: 0.357 AC XY: 26338 AN XY: 73864

Gnomad4 AFR AF: 0.453

Gnomad4 AMR AF: 0.448

Gnomad4 ASJ AF: 0.243

Gnomad4 EAS AF: 0.555

Gnomad4 SAS AF: 0.347

Gnomad4 FIN AF: 0.289

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.362

Alfa AF: 0.204 Hom.: 535

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 13, 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
BranchPoint Hunter		1.0

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: rs11414268; hg19: chr14-51375699;