rs113993979

Variant names:

• chr14-50915373-C-G
• NM_002863.5:c.1366G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-50915373-C-G
• chr14-50915373-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_002863.5(PYGL):​c.1366G>C​(p.Val456Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V456M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PYGL NM_002863.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-50915373-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGL	NM_002863.5	c.1366G>C	p.Val456Leu	missense_variant	Exon 11 of 20	ENST00000216392.8	NP_002854.3
PYGL	NM_001163940.2	c.1264G>C	p.Val422Leu	missense_variant	Exon 10 of 19		NP_001157412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGL	ENST00000216392.8	c.1366G>C	p.Val456Leu	missense_variant	Exon 11 of 20	1	NM_002863.5	ENSP00000216392.7
PYGL	ENST00000532462.5	c.1366G>C	p.Val456Leu	missense_variant	Exon 11 of 20	1		ENSP00000431657.1
PYGL	ENST00000544180.6	c.1264G>C	p.Val422Leu	missense_variant	Exon 10 of 19	2		ENSP00000443787.1
PYGL	ENST00000528757.2	n.243G>C		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	.;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	.;.;H
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.011	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.85
MutPred		0.91		Loss of catalytic residue at V456 (P = 0.0556);.;Loss of catalytic residue at V456 (P = 0.0556);
MVP		0.97
MPC		0.14
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-51382091;