Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003560.4(PLA2G6):c.172G>A(p.Val58Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,614,124 control chromosomes in the GnomAD database, including 100 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V58V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 48 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 52 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.18

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004707277).

BP6

Variant 22-38169255-C-T is Benign according to our data. Variant chr22-38169255-C-T is described in ClinVar as Benign. ClinVar VariationId is 159745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0138 (2100/152338) while in subpopulation AFR AF = 0.0478 (1986/41576). AF 95% confidence interval is 0.046. There are 48 homozygotes in GnomAd4. There are 992 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 48 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003560.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLA2G6	NM_003560.4	MANE Select	c.172G>A	p.Val58Ile	missense	Exon 2 of 17	NP_003551.2
PLA2G6	NM_001349864.2		c.172G>A	p.Val58Ile	missense	Exon 2 of 17	NP_001336793.1
PLA2G6	NM_001004426.3		c.172G>A	p.Val58Ile	missense	Exon 2 of 16	NP_001004426.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLA2G6	ENST00000332509.8	TSL:1 MANE Select	c.172G>A	p.Val58Ile	missense	Exon 2 of 17	ENSP00000333142.3
PLA2G6	ENST00000402064.5	TSL:1	c.172G>A	p.Val58Ile	missense	Exon 2 of 16	ENSP00000386100.1
PLA2G6	ENST00000668949.1		c.172G>A	p.Val58Ile	missense	Exon 2 of 17	ENSP00000499711.1

Frequencies

GnomAD3 genomes

AF:

0.0138

AC:

2096

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0478

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00563

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00812

GnomAD2 exomes

AF:

0.00359

AC:

899

AN:

250748

AF XY:

0.00266

show subpopulations

Gnomad AFR exome

AF:

0.0502

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000883

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00153

AC:

2237

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

944

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.0511

AC:

1709

AN:

33476

American (AMR)

AF:

0.00226

AC:

101

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.000232

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000156

AC:

173

AN:

1111954

Other (OTH)

AF:

0.00373

AC:

225

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

120

239

359

478

598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.0138

AC:

2100

AN:

152338

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

992

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0478

AC:

1986

AN:

41576

American (AMR)

AF:

0.00562

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68030

Other (OTH)

AF:

0.00803

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

188

282

376

470

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00328

Hom.:

Bravo

AF:

0.0149

ESP6500AA

AF:

0.0409

AC:

180

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00418

AC:

507

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Infantile neuroaxonal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.43

CADD

Benign

4.3

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.14

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0047

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.17

PhyloP100

-1.2

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.34

REVEL

Benign

0.056

Sift

Benign

0.28

Sift4G

Benign

0.24

Polyphen

0.013

Vest4

0.060

MVP

0.37

MPC

0.20

ClinPred

0.0040

GERP RS

-9.6

Varity_R

0.022

gMVP

0.39

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over