22-38169336-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_003560.4(PLA2G6):c.91G>A(p.Asp31Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,614,118 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_003560.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000342 AC: 52AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000458 AC: 115AN: 251242Hom.: 0 AF XY: 0.000390 AC XY: 53AN XY: 135800
GnomAD4 exome AF: 0.000447 AC: 654AN: 1461828Hom.: 1 Cov.: 32 AF XY: 0.000441 AC XY: 321AN XY: 727226
GnomAD4 genome AF: 0.000341 AC: 52AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24AN XY: 74470
ClinVar
Submissions by phenotype
not provided Uncertain:4
PLA2G6: PM2, BP4 -
No Applicable ACMG Criteria -
BP4 -
Reported previously in two siblings with adult-onset Parkinson disease; however, a second PLA2G6 variant was not detected and information regarding parental testing was not available (PMID: 30042723); Observed in patient with brain iron accumulation in published literature; however, a pathogenic variant in another gene was also identified (PMID: 30169597); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25294124, 32771225, 30042723, 37750340, 30169597) -
Inborn genetic diseases Uncertain:1
The c.91G>A (p.D31N) alteration is located in exon 2 (coding exon 1) of the PLA2G6 gene. This alteration results from a G to A substitution at nucleotide position 91, causing the aspartic acid (D) at amino acid position 31 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
PLA2G6-associated neurodegeneration Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Infantile neuroaxonal dystrophy;C1857747:Neurodegeneration with brain iron accumulation 2B;C2751842:Autosomal recessive Parkinson disease 14 Uncertain:1
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Infantile neuroaxonal dystrophy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at