chr22-38112565-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_003560.4(PLA2G6):ā€‹c.2215G>Cā€‹(p.Asp739His) variant causes a missense change. The variant allele was found at a frequency of 0.0000367 in 1,552,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.000039 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

7
11
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:3

Conservation

PhyloP100: 7.05
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.965
PP5
Variant 22-38112565-C-G is Pathogenic according to our data. Variant chr22-38112565-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159761.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=3, Likely_pathogenic=3}. Variant chr22-38112565-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLA2G6NM_003560.4 linkc.2215G>C p.Asp739His missense_variant Exon 16 of 17 ENST00000332509.8 NP_003551.2 O60733-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PLA2G6ENST00000332509.8 linkc.2215G>C p.Asp739His missense_variant Exon 16 of 17 1 NM_003560.4 ENSP00000333142.3 O60733-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152126
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000130
AC:
2
AN:
153362
Hom.:
0
AF XY:
0.0000244
AC XY:
2
AN XY:
81882
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000343
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000386
AC:
54
AN:
1400246
Hom.:
0
Cov.:
31
AF XY:
0.0000448
AC XY:
31
AN XY:
691276
show subpopulations
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:
0.0000481
Gnomad4 OTH exome
AF:
0.0000344
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152126
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74310
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Jan 10, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP3, PM2_moderate, PM3_supporting, PS4_moderate -

Mar 14, 2022
AiLife Diagnostics, AiLife Diagnostics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 23, 2024
GeneDx
Significance: 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 has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16783378, 30120687, 18799783) -

PLA2G6-associated neurodegeneration Uncertain:2
Jan 24, 2023
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.Asp739His variant in PLA2G6 has been reported in 2 individuals with PLA2G6-associated neurodegeneration (PMID: 30120687, 18799783), segregated with disease in 1 affected relative from 1 family (PMID: 18799783), and has been identified in 0.006% (1/17170) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784349). 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 (Variation ID#: 159761) and has been interpreted as a variant of uncertain significance by Illumina Laboratory Services and Invitae, and pathogenic by GeneDx and Genetic Services Laboratory (University of Chicago). Of the 2 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.Asp739His variant is pathogenic (PMID: 30120687). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Asp739His variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PP3, PM3_supporting (Richards 2015). -

Jun 14, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The PLA2G6 c.2215G>C (p.Asp739His) variant has been reported in a compound heterozygous state with another missense variant in two related patients with atypical neuroaxonal dystrophy, which was initially categorized as idiopathic neurodegeneration with brain iron accumulation (Morgan et al. 2006; Gregory et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.00002 in the Total population of the Genome Aggregation Database. The evidence for this variant is limited. The p.Asp739His variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for PLA2G6-associated neurodegeneration. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Infantile neuroaxonal dystrophy Pathogenic:1
Jan 28, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 739 of the PLA2G6 protein (p.Asp739His). This variant is present in population databases (rs587784349, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of PLA2G6-related conditions (PMID: 16783378; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 159761). 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 expected to disrupt PLA2G6 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Iron accumulation in brain Pathogenic:1
Feb 08, 2013
Genetic Services Laboratory, University of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Infantile neuroaxonal dystrophy;C1857747:Neurodegeneration with brain iron accumulation 2B;C2751842:Autosomal recessive Parkinson disease 14 Pathogenic:1
Feb 02, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1
Jun 13, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2215G>C (p.D739H) alteration is located in exon 16 (coding exon 15) of the PLA2G6 gene. This alteration results from a G to C substitution at nucleotide position 2215, causing the aspartic acid (D) at amino acid position 739 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.32
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.64
D;.;.
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;.
M_CAP
Pathogenic
0.56
D
MetaRNN
Pathogenic
0.96
D;D;D
MetaSVM
Uncertain
0.43
D
MutationAssessor
Uncertain
2.5
M;.;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-4.2
D;D;D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.0040
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.96
MutPred
0.81
Loss of loop (P = 0.0073);.;.;
MVP
0.95
MPC
0.90
ClinPred
0.97
D
GERP RS
4.5
Varity_R
0.67
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587784349; hg19: chr22-38508572; API