chr22-38123180-C-G

Variant names:

• chr22-38123180-C-G
• rs1555988382
• NM_003560.4:c.1506G>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4
• 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]

ACMG classification

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, 7 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=4, Likely_pathogenic=2}. Variant chr22-38123180-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLA2G6	NM_003560.4	c.1506G>C	p.Lys502Asn	missense_variant	Exon 11 of 17	ENST00000332509.8	NP_003551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8	c.1506G>C	p.Lys502Asn	missense_variant	Exon 11 of 17	1	NM_003560.4	ENSP00000333142.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000243 AC: 34 AN: 1400046 Hom.: 0 Cov.: 32 AF XY: 0.0000217 AC XY: 15 AN XY: 690670

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Infantile neuroaxonal dystrophy Uncertain:2

Feb 28, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 502 of the PLA2G6 protein (p.Lys502Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of infantile neuroaxonal dystrophy (PMID: 16783378, 29915382). ClinVar contains an entry for this variant (Variation ID: 436320). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PLA2G6 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. -

not provided Pathogenic:1

Oct 30, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 20, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Oct 26, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

PLA2G6-associated neurodegeneration Uncertain:1

Apr 30, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Lys502Asn variant in PLA2G6 has been reported in 3 individuals with PLA2G6-associated neurodegeneration (PMID: 16783378, 29915382, 18799783), and has been identified in 0.003% (33/1147958) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs370691849). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VCV000436320.10) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago) and GeneDx, and a variant of uncertain significance by Baylor Genetics and Women's Health and Genetics/Laboratory Corporation of America. Of the 3 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Lys502Asn variant is pathogenic (VCV000159749.25; PMID: 18799783). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Lys502Asn variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PM3_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D;D;.
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.065	B;D;D
Vest4		0.79
MutPred		0.83		Gain of helix (P = 0.0034);.;.;
MVP		0.80
MPC		0.73
ClinPred		0.90	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555988382; hg19: chr22-38519187;