22-38132881-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_003560.4(PLA2G6):c.1027G>A(p.Ala343Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,553,716 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A343V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0092 ( 6 hom., cov: 33)

Exomes 𝑓: 0.012 ( 136 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.26

Publications

20 publications found

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]

PLA2G6 Gene-Disease associations (from GenCC):

neurodegeneration with brain iron accumulation 2A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
neurodegeneration with brain iron accumulation 2B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
PLA2G6-associated neurodegeneration
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive Parkinson disease 14
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

PLA2G6 links:

ENSG00000279080 (HGNC:):

ENSG00000279080 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003560.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0031460226).

BP6

Variant 22-38132881-C-T is Benign according to our data. Variant chr22-38132881-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00918 (1399/152360) while in subpopulation SAS AF = 0.0153 (74/4828). AF 95% confidence interval is 0.0125. There are 6 homozygotes in GnomAd4. There are 699 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLA2G6	NM_003560.4 link	c.1027G>A	p.Ala343Thr	missense_variant	Exon 7 of 17	ENST00000332509.8	NP_003551.2	O60733-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8 link	c.1027G>A	p.Ala343Thr	missense_variant	Exon 7 of 17	1	NM_003560.4	ENSP00000333142.3		O60733-1

Frequencies

GnomAD3 genomes

AF:

0.00920

AC:

1401

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.0538

Gnomad AMR

AF:

0.00890

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.00715

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0131

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0110

AC:

1757

AN:

159972

AF XY:

0.0121

show subpopulations

Gnomad AFR exome

AF:

0.00254

Gnomad AMR exome

AF:

0.00577

Gnomad ASJ exome

AF:

0.0197

Gnomad EAS exome

AF:

0.000169

Gnomad FIN exome

AF:

0.00808

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.0142

GnomAD4 exome

AF:

0.0121

AC:

16997

AN:

1401356

Hom.:

136

Cov.:

AF XY:

0.0125

AC XY:

8670

AN XY:

691800

show subpopulations

African (AFR)

AF:

0.00205

AC:

AN:

31776

American (AMR)

AF:

0.00645

AC:

234

AN:

36306

Ashkenazi Jewish (ASJ)

AF:

0.0174

AC:

438

AN:

25180

East Asian (EAS)

AF:

0.000139

AC:

AN:

36008

South Asian (SAS)

AF:

0.0158

AC:

1253

AN:

79478

European-Finnish (FIN)

AF:

0.00716

AC:

340

AN:

47462

Middle Eastern (MID)

AF:

0.0289

AC:

160

AN:

5528

European-Non Finnish (NFE)

AF:

0.0128

AC:

13823

AN:

1081474

Other (OTH)

AF:

0.0117

AC:

679

AN:

58144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

975

1950

2925

3900

4875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

518

1036

1554

2072

2590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00918

AC:

1399

AN:

152360

Hom.:

Cov.:

AF XY:

0.00938

AC XY:

699

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

41590

American (AMR)

AF:

0.00888

AC:

136

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0153

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00715

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0131

AC:

894

AN:

68030

Other (OTH)

AF:

0.0109

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

144

215

287

359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0128

Hom.:

Bravo

AF:

0.00952

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00208

AC:

ESP6500EA

AF:

0.0128

AC:

109

ExAC

AF:

0.00664

AC:

750

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Apr 01, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25174650, 27393345, 30340910) -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PLA2G6: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:5

Jan 31, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Infantile neuroaxonal dystrophy

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PLA2G6-related disorder

Benign:1

Oct 15, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Parkinson disease;C0242422:Parkinsonian disorder;C0393568:Vascular parkinsonism

Benign:1

Oct 01, 2024

The Egyptian Network for Neurodegenerative Diseases (ENND), The American University in Cairo

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

This rare variant (MAF 0.00559105/0.0085 in 1000Genomes/GnomAD) falls within Ankyrin repeat-containing domain. No available functional characterization but nearest amino acid substituition 2 amino acids away A341T causes PLA2G6-associated neurodegeneration (PLAN) and a complete loss of phospholipase and lysophospholipase activities. Heterozygous p.Ser258Leu, also within ANK repeat domain, is reported in late-onset parkinsonism. We observed the same amino acid substituted in 3/5 vascular parkinsonism patients; via 2 different variants. This variant was observed in 2 patients and is an eQTL for NPTXR in brain tissue, a biomarker of synaptic dysfunction associated with multiple neurodegenerative diseases including PD, and reported to be decreased in atypical parkinsonian disorders. While PLA2G6 parkinsonism cases are mostly bi-allelic, several cases of mono-allelic variant carriers -of other PLA2G6 variants- have been reported in atypical parkinsonism (PMID:34307755;30042723). CAD score is 20.3. -

PLA2G6-associated neurodegeneration

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.87

D;D;.

MetaRNN

Benign

0.0031

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.37

N;N;N

PhyloP100

1.3

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.021

Sift

Benign

0.30

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.032

B;B;B

Vest4

0.12

MPC

0.26

ClinPred

0.017

GERP RS

3.1

Varity_R

0.052

gMVP

0.76

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over