rs200133000
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The NM_000298.6(PKLR):c.1468C>T(p.Arg490Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000905 in 1,613,660 control chromosomes in the GnomAD database, including 2 homozygotes. 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. R490Q) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000090 ( 2 hom. )
Consequence
PKLR
NM_000298.6 missense
NM_000298.6 missense
Scores
12
5
1
Clinical Significance
Conservation
PhyloP100: 6.70
Genes affected
PKLR (HGNC:9020): (pyruvate kinase L/R) The protein encoded by this gene is a pyruvate kinase that catalyzes the transphosphorylation of phohsphoenolpyruvate into pyruvate and ATP, which is the rate-limiting step of glycolysis. Defects in this enzyme, due to gene mutations or genetic variations, are the common cause of chronic hereditary nonspherocytic hemolytic anemia (CNSHA or HNSHA). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000298.6
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKLR | NM_000298.6 | c.1468C>T | p.Arg490Trp | missense_variant | 10/11 | ENST00000342741.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKLR | ENST00000342741.6 | c.1468C>T | p.Arg490Trp | missense_variant | 10/11 | 1 | NM_000298.6 | P3 | |
PKLR | ENST00000392414.7 | c.1375C>T | p.Arg459Trp | missense_variant | 10/11 | 1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152168Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000127 AC: 32AN: 251286Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135844
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GnomAD4 exome AF: 0.0000903 AC: 132AN: 1461374Hom.: 2 Cov.: 33 AF XY: 0.0000894 AC XY: 65AN XY: 726992
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GnomAD4 genome ? AF: 0.0000919 AC: 14AN: 152286Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 8AN XY: 74462
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 30, 2022 | 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. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 292806). This missense change has been observed in individuals with pyruvate kinase deficiency (PMID: 7702630; Invitae). This variant is present in population databases (rs200133000, gnomAD 0.1%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 490 of the PKLR protein (p.Arg490Trp). - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 26, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 13, 2023 | - - |
Pyruvate kinase deficiency of red cells Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The PKLR c.1468C>T (p.Arg490Trp) missense variant has been reported in at least two studies in which it was found in a compound heterozygous state with another missense variant in one individual with pyruvate kinase deficiency (Uenaka et al. 1995). Among 3,785 control individuals, the p.Arg490Trp variant was found in a heterozygous state in 2/126 individuals from the Asian population (Beutler et al. 2000). The variant is also reported at a frequency of 0.00174 in the East Asian population of the Exome Aggregation Consortium. The Arg490 residue is well conserved and is located in a region thought to be involved in ADP binding and intersubunit contacts. The evidence for this variant is limited. The p.Arg490Trp variant is therefore classified as a variant of unknown significance, but suspicious for pathogenicity for pyruvate kinase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at