rs1555988382
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5
The NM_003560.4(PLA2G6):c.1506G>C(p.Lys502Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000243 in 1,400,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
PLA2G6
NM_003560.4 missense
NM_003560.4 missense
Scores
10
9
Clinical Significance
Conservation
PhyloP100: 0.607
Genes affected
PLA2G6 (HGNC:9039): (phospholipase A2 group VI) The protein encoded by this gene is an A2 phospholipase, a class of enzyme that catalyzes the release of fatty acids from phospholipids. The encoded protein may play a role in phospholipid remodelling, arachidonic acid release, leukotriene and prostaglandin synthesis, fas-mediated apoptosis, and transmembrane ion flux in glucose-stimulated B-cells. Several transcript variants encoding multiple isoforms have been described, but the full-length nature of only three of them have been determined to date. [provided by RefSeq, Dec 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_003560.4
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 22-38123180-C-G is Pathogenic according to our data. Variant chr22-38123180-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436320.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}. Variant chr22-38123180-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLA2G6 | NM_003560.4 | c.1506G>C | p.Lys502Asn | missense_variant | 11/17 | ENST00000332509.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLA2G6 | ENST00000332509.8 | c.1506G>C | p.Lys502Asn | missense_variant | 11/17 | 1 | NM_003560.4 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.0000243 AC: 34AN: 1400046Hom.: 0 Cov.: 32 AF XY: 0.0000217 AC XY: 15AN XY: 690670
GnomAD4 exome
AF:
AC:
34
AN:
1400046
Hom.:
Cov.:
32
AF XY:
AC XY:
15
AN XY:
690670
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32357911, 18799783, 29915382, 16783378) - |
Neurodegeneration with brain iron accumulation 2B Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 20, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 26, 2023 | Variant summary: PLA2G6 c.1506G>C (p.Lys502Asn) results in a non-conservative amino acid change located in the patatin-like phospholipase domain (IPR002641) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 158944 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1506G>C has been reported in the literature as a compound heterozygous genotype in at least two individuals affected with classical infantile neuroaxonal dystrophy (e.g. Morgan_2006, Gregory_2008). However, it has also been reported in a child who underwent WES for an ataxia of unknown etiology who was found to have a nonsense variant in trans and an exon 3-6 deletion in cis with the variant, providing possible evidence for a benign role (Sun_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18799783, 16783378, 29915382). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Infantile neuroaxonal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 28, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;D;D
Vest4
MutPred
Gain of helix (P = 0.0034);.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at