rs11414268

Variant names:

• chr14-50908981-TA-T
• rs11414268
• NM_002863.5:c.2178-27delT

Your query was ambiguous. Multiple possible variants found:

• chr14-50908981-TA-T
• chr14-50908981-TA-TAA
• chr14-50908981-TA-TAAA
• chr14-50908981-TA-TAAAAAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002863.5(PYGL):​c.2178-27delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,383,860 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000087 (0 hom.)
• Consequence: PYGL NM_002863.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.780
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002863.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGL	NM_002863.5	MANE Select	c.2178-27delT		intron	N/A	NP_002854.3
	PYGL	NM_001163940.2		c.2076-27delT		intron	N/A	NP_001157412.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGL	ENST00000216392.8	TSL:1 MANE Select	c.2178-27delT		intron	N/A	ENSP00000216392.7
	PYGL	ENST00000532462.5	TSL:1	c.2178-27delT		intron	N/A	ENSP00000431657.1
	PYGL	ENST00000874287.1		c.2193-27delT		intron	N/A	ENSP00000544346.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000867 AC: 12 AN: 1383860 Hom.: 0 Cov.: 33 AF XY: 0.0000101 AC XY: 7 AN XY: 691946

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30994

American (AMR) AF: 0.00 AC: 0 AN: 43976

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25416

East Asian (EAS) AF: 0.00 AC: 0 AN: 37986

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5600

European-Non Finnish (NFE) AF: 0.00000955 AC: 10 AN: 1046934

Other (OTH) AF: 0.00 AC: 0 AN: 57144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000540874), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.78
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

Other links and lift over

dbSNP: rs11414268; hg19: chr14-51375699;