chr22-38112165-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003560.4(PLA2G6):ā€‹c.2417C>Gā€‹(p.Pro806Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000513 in 1,581,658 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P806S) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.00045 ( 0 hom., cov: 32)
Exomes š‘“: 0.00052 ( 3 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

2
3
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 2.36
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 Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0078371465).
BP6
Variant 22-38112165-G-C is Benign according to our data. Variant chr22-38112165-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211910.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=5}. Variant chr22-38112165-G-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000453 (69/152312) while in subpopulation EAS AF= 0.011 (57/5184). AF 95% confidence interval is 0.00871. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PLA2G6NM_003560.4 linkuse as main transcriptc.2417C>G p.Pro806Arg missense_variant 17/17 ENST00000332509.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PLA2G6ENST00000332509.8 linkuse as main transcriptc.2417C>G p.Pro806Arg missense_variant 17/171 NM_003560.4 P3O60733-1

Frequencies

GnomAD3 genomes
AF:
0.000453
AC:
69
AN:
152194
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0110
Gnomad SAS
AF:
0.00186
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000856
AC:
169
AN:
197464
Hom.:
2
AF XY:
0.000783
AC XY:
83
AN XY:
106052
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00995
Gnomad SAS exome
AF:
0.000275
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000117
Gnomad OTH exome
AF:
0.000968
GnomAD4 exome
AF:
0.000520
AC:
743
AN:
1429346
Hom.:
3
Cov.:
31
AF XY:
0.000517
AC XY:
366
AN XY:
708064
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000785
Gnomad4 EAS exome
AF:
0.0151
Gnomad4 SAS exome
AF:
0.000575
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000812
Gnomad4 OTH exome
AF:
0.000541
GnomAD4 genome
AF:
0.000453
AC:
69
AN:
152312
Hom.:
0
Cov.:
32
AF XY:
0.000537
AC XY:
40
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0110
Gnomad4 SAS
AF:
0.00186
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000545
Hom.:
1
Bravo
AF:
0.000559
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000788
AC:
95
Asia WGS
AF:
0.00606
AC:
21
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:8
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:5
Likely benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 08, 2021This variant is associated with the following publications: (PMID: 23182313, 30232368, 30065071, 27942883, 21368765, 21812034, 22213678) -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsDec 03, 2018- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2023PLA2G6: BS1 -
Autosomal recessive Parkinson disease 14 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingDepartment of Neurology, Xijing Hospital, Fourth Military Medical UniversityMar 01, 2022- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMar 10, 2020- -
Infantile neuroaxonal dystrophy Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
PLA2G6-associated neurodegeneration Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.31
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
T;.;.
Eigen
Benign
0.040
Eigen_PC
Benign
-0.015
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.84
T;T;.
MetaRNN
Benign
0.0078
T;T;T
MetaSVM
Benign
-0.67
T
MutationAssessor
Benign
1.8
L;.;.
MutationTaster
Benign
0.75
D;D;D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-1.5
N;N;N
REVEL
Benign
0.12
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;P;P
Vest4
0.21
MVP
0.79
MPC
0.91
ClinPred
0.081
T
GERP RS
3.3
Varity_R
0.097
gMVP
0.35

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: rs140758033; hg19: chr22-38508172; API