NM_005609.4:c.2143C>G

Variant names:

• chr11-64750410-G-C
• rs780656375
• NM_005609.4:c.2143C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP3

The NM_005609.4(PYGM):​c.2143C>G​(p.Arg715Gly) 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. R715W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PYGM NM_005609.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.719
• Publications: 6 publications found

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]

PYGM Gene-Disease associations (from GenCC):

• glycogen storage disease V

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64750410-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 555145.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 37 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 0.046884 (below the threshold of 3.09). Trascript score misZ: 1.6804 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease V.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005609.4. 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
	PYGM	NM_005609.4	MANE Select	c.2143C>G	p.Arg715Gly	missense	Exon 17 of 20	NP_005600.1	P11217-1
	PYGM	NM_001164716.1		c.1879C>G	p.Arg627Gly	missense	Exon 15 of 18	NP_001158188.1	P11217-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGM	ENST00000164139.4	TSL:1 MANE Select	c.2143C>G	p.Arg715Gly	missense	Exon 17 of 20	ENSP00000164139.3	P11217-1
	PYGM	ENST00000967737.1		c.2242C>G	p.Arg748Gly	missense	Exon 18 of 21	ENSP00000637796.1
	PYGM	ENST00000938870.1		c.2059C>G	p.Arg687Gly	missense	Exon 17 of 20	ENSP00000608929.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		0.72
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.70
Sift	Benign	0.18	T
Sift4G	Uncertain	0.052	T
Polyphen		0.020	B
Vest4		0.89
MutPred		0.57		Gain of catalytic residue at V716 (P = 0.0973)
MVP		0.91
MPC		0.92
ClinPred		0.99	D
GERP RS		2.7
Varity_R		0.85
gMVP		0.84
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs780656375; hg19: chr11-64517882;