Genetic Variant NM_005609.4:c.924C>G (chr11-64754768-G-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_005609.4(PYGM):c.924C>G(p.Ile308Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I308I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PYGM
NM_005609.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.83

Publications

0 publications found

Variant links:

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

PYGM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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, 0.906

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.924C>G	p.Ile308Met	missense	Exon 8 of 20	NP_005600.1	P11217-1
	PYGM	NM_001164716.1		c.660C>G	p.Ile220Met	missense	Exon 6 of 18	NP_001158188.1	P11217-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PYGM	ENST00000164139.4	TSL:1 MANE Select	c.924C>G	p.Ile308Met	missense	Exon 8 of 20	ENSP00000164139.3	P11217-1
PYGM	ENST00000967737.1		c.1023C>G	p.Ile341Met	missense	Exon 9 of 21	ENSP00000637796.1
PYGM	ENST00000938870.1		c.840C>G	p.Ile280Met	missense	Exon 8 of 20	ENSP00000608929.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461622

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111974

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

0.80

MutationAssessor

Uncertain

2.4

PhyloP100

4.8

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.81

Sift

Benign

0.097

Sift4G

Benign

0.20

Polyphen

0.16

Vest4

0.93

MutPred

0.75

Loss of methylation at K313 (P = 0.0985)

MVP

0.97

MPC

0.82

ClinPred

0.93

GERP RS

4.0

Varity_R

0.45

gMVP

0.78

Mutation Taster

=45/55

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over