rs143177272
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_005609.4(PYGM):c.2446C>T(p.Arg816Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000991 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R816H) has been classified as Uncertain significance.
Frequency
Consequence
NM_005609.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PYGM | NM_005609.4 | c.2446C>T | p.Arg816Cys | missense_variant | 20/20 | ENST00000164139.4 | |
PYGM | NM_001164716.1 | c.2182C>T | p.Arg728Cys | missense_variant | 18/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PYGM | ENST00000164139.4 | c.2446C>T | p.Arg816Cys | missense_variant | 20/20 | 1 | NM_005609.4 | P1 | |
PYGM | ENST00000377432.7 | c.2182C>T | p.Arg728Cys | missense_variant | 18/18 | 2 | |||
PYGM | ENST00000483742.1 | n.1799C>T | non_coding_transcript_exon_variant | 3/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152144Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251484Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135918
GnomAD4 exome AF: 0.0000985 AC: 144AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.000102 AC XY: 74AN XY: 727248
GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152144Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7AN XY: 74322
ClinVar
Submissions by phenotype
Glycogen storage disease, type V Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 26, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 816 of the PYGM protein (p.Arg816Cys). This variant is present in population databases (rs143177272, gnomAD 0.009%). 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: 281389). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Tip-toe gait Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino | Oct 26, 2021 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 25, 2022 | The c.2446C>T (p.R816C) alteration is located in exon 20 (coding exon 20) of the PYGM gene. This alteration results from a C to T substitution at nucleotide position 2446, causing the arginine (R) at amino acid position 816 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 11, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at