chr11-64759751-G-C

Position:

• chr11-64759751-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000164139.4(PYGM):​c.148C>G​(p.Arg50Gly) variant causes a missense change involving the alteration of a non-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. R50Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PYGM ENST00000164139.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56

Genes affected

PYGM (HGNC:9726): (glycogen phosphorylase, muscle associated) This gene encodes a muscle enzyme involved in glycogenolysis. Highly similar enzymes encoded by different genes are found in liver and brain. Mutations in this gene are associated with McArdle disease (myophosphorylase deficiency), a glycogen storage disease of muscle. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGM	NM_005609.4	c.148C>G	p.Arg50Gly	missense_variant	1/20	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.148C>G	p.Arg50Gly	missense_variant	1/18		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.148C>G	p.Arg50Gly	missense_variant	1/20	1	NM_005609.4	ENSP00000164139	P1
PYGM	ENST00000377432.7	c.148C>G	p.Arg50Gly	missense_variant	1/18	2		ENSP00000366650

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	.;T
Eigen	Benign	0.062
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.71
Sift	Benign	0.092	T;T
Sift4G	Benign	0.094	T;T
Polyphen		0.98	.;D
Vest4		0.78
MutPred		0.47		Gain of catalytic residue at R50 (P = 0.0591);Gain of catalytic residue at R50 (P = 0.0591);
MVP		0.92
MPC		0.75
ClinPred		0.99	D
GERP RS		2.4
Varity_R		0.79
gMVP		0.75

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: rs116987552; hg19: chr11-64527223;