rs76718524
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_003560.4(PLA2G6):c.1381C>T(p.Arg461Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,613,576 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R461Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_003560.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLA2G6 | NM_003560.4 | c.1381C>T | p.Arg461Trp | missense_variant | 10/17 | ENST00000332509.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLA2G6 | ENST00000332509.8 | c.1381C>T | p.Arg461Trp | missense_variant | 10/17 | 1 | NM_003560.4 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 26AN: 152106Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000144 AC: 36AN: 250548Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135550
GnomAD4 exome AF: 0.000170 AC: 249AN: 1461352Hom.: 0 Cov.: 30 AF XY: 0.000158 AC XY: 115AN XY: 726982
GnomAD4 genome AF: 0.000171 AC: 26AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13AN XY: 74418
ClinVar
Submissions by phenotype
Infantile neuroaxonal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 04, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 461 of the PLA2G6 protein (p.Arg461Trp). This variant is present in population databases (rs76718524, gnomAD 0.02%). This missense change has been observed in individual(s) with early-onset Parkinson disease (PMID: 21812034). ClinVar contains an entry for this variant (Variation ID: 459996). 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 expected to disrupt PLA2G6 protein function. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 10, 2022 | Previously reported in the heterozygous state in an individual with early onset Parkinson disease; variant was also observed in an individual in the control population (Kauther et al., 2011).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22575062, 21812034) - |
Infantile neuroaxonal dystrophy;C1857747:Neurodegeneration with brain iron accumulation 2B;C2751842:Autosomal recessive Parkinson disease 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 07, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at