rs144399762
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2
The NM_000291.4(PGK1):āc.736A>Gā(p.Lys246Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 112,237 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000291.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PGK1 | NM_000291.4 | c.736A>G | p.Lys246Glu | missense_variant | 7/11 | ENST00000373316.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PGK1 | ENST00000373316.5 | c.736A>G | p.Lys246Glu | missense_variant | 7/11 | 1 | NM_000291.4 | P1 | |
PGK1 | ENST00000474281.1 | n.91A>G | non_coding_transcript_exon_variant | 1/2 | 1 | ||||
PGK1 | ENST00000644362.1 | c.652A>G | p.Lys218Glu | missense_variant | 7/11 | ||||
PGK1 | ENST00000491291.1 | downstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000357 AC: 4AN: 112184Hom.: 0 Cov.: 23 AF XY: 0.0000582 AC XY: 2AN XY: 34338
GnomAD3 exomes AF: 0.0000164 AC: 3AN: 183432Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67886
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000124 AC: 13AN: 1045256Hom.: 0 Cov.: 26 AF XY: 0.0000126 AC XY: 4AN XY: 317770
GnomAD4 genome ? AF: 0.0000356 AC: 4AN: 112237Hom.: 0 Cov.: 23 AF XY: 0.0000581 AC XY: 2AN XY: 34401
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 246 of the PGK1 protein (p.Lys246Glu). This variant is present in population databases (rs144399762, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PGK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 591102). 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 PGK1 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. - |
Uncertain significance, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 02, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at