rs200118962

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_005609.4(PYGM):​c.2500C>T​(p.Arg834Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R834G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

PYGM
NM_005609.4 missense

Scores

1
11
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.27

Publications

3 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: STRONG, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

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.
BP4
Computational evidence support a benign effect (MetaRNN=0.25591987).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PYGMNM_005609.4 linkc.2500C>T p.Arg834Cys missense_variant Exon 20 of 20 ENST00000164139.4 NP_005600.1 P11217-1
PYGMNM_001164716.1 linkc.2236C>T p.Arg746Cys missense_variant Exon 18 of 18 NP_001158188.1 P11217-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PYGMENST00000164139.4 linkc.2500C>T p.Arg834Cys missense_variant Exon 20 of 20 1 NM_005609.4 ENSP00000164139.3 P11217-1
PYGMENST00000377432.7 linkc.2236C>T p.Arg746Cys missense_variant Exon 18 of 18 2 ENSP00000366650.3 P11217-2
PYGMENST00000483742.1 linkn.1853C>T non_coding_transcript_exon_variant Exon 3 of 3 2

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.000956
GnomAD2 exomes
AF:
0.0000875
AC:
22
AN:
251400
AF XY:
0.0000883
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000318
Gnomad ASJ exome
AF:
0.000397
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.0000342
AC:
50
AN:
1461882
Hom.:
0
Cov.:
31
AF XY:
0.0000358
AC XY:
26
AN XY:
727244
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.000291
AC:
13
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.000421
AC:
11
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53408
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000180
AC:
20
AN:
1112012
Other (OTH)
AF:
0.0000662
AC:
4
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
Heterozygous variant carriers
0
4
8
11
15
19
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
AF:
0.0000394
AC:
6
AN:
152204
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74352
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41456
American (AMR)
AF:
0.000131
AC:
2
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68038
Other (OTH)
AF:
0.000956
AC:
2
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000450
Hom.:
0
Bravo
AF:
0.0000793
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Glycogen storage disease, type V Uncertain:3
Jul 30, 2021
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

May 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 834 of the PYGM protein (p.Arg834Cys). This variant is present in population databases (rs200118962, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PYGM-related conditions. ClinVar contains an entry for this variant (Variation ID: 2197078). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PYGM protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Feb 08, 2021
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.055
T
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.37
.;T
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.26
T;T
MetaSVM
Uncertain
0.46
D
MutationAssessor
Benign
1.6
.;L
PhyloP100
3.3
PrimateAI
Benign
0.43
T
PROVEAN
Uncertain
-3.6
D;D
REVEL
Uncertain
0.55
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
0.98
.;D
Vest4
0.31
MVP
0.93
MPC
0.30
ClinPred
0.21
T
GERP RS
4.4
Varity_R
0.58
gMVP
0.58
Mutation Taster
=52/48
polymorphism

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

Other links and lift over

dbSNP: rs200118962; hg19: chr11-64514160; API