Genetic Variant NM_003560.4:c.2417C>G (chr22-38112165-G-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003560.4(PLA2G6):c.2417C>G(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. 13/21 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: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00052 ( 3 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.36

Publications

13 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 -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 VariationId is 211910.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 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.2417C>G	p.Pro806Arg	missense	Exon 17 of 17	NP_003551.2
PLA2G6	NM_001349864.2		c.2417C>G	p.Pro806Arg	missense	Exon 17 of 17	NP_001336793.1
PLA2G6	NM_001004426.3		c.2255C>G	p.Pro752Arg	missense	Exon 16 of 16	NP_001004426.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLA2G6	ENST00000332509.8	TSL:1 MANE Select	c.2417C>G	p.Pro806Arg	missense	Exon 17 of 17	ENSP00000333142.3
PLA2G6	ENST00000402064.5	TSL:1	c.2255C>G	p.Pro752Arg	missense	Exon 16 of 16	ENSP00000386100.1
PLA2G6	ENST00000668949.1		c.2459C>G	p.Pro820Arg	missense	Exon 17 of 17	ENSP00000499711.1

Frequencies

GnomAD3 genomes

AF:

0.000453

AC:

AN:

152194

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000856

AC:

169

AN:

197464

AF XY:

0.000783

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 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.:

Cov.:

AF XY:

0.000517

AC XY:

366

AN XY:

708064

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32838

American (AMR)

AF:

0.00

AC:

AN:

39556

Ashkenazi Jewish (ASJ)

AF:

0.0000785

AC:

AN:

25462

East Asian (EAS)

AF:

0.0151

AC:

572

AN:

37938

South Asian (SAS)

AF:

0.000575

AC:

AN:

81736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50994

Middle Eastern (MID)

AF:

0.000187

AC:

AN:

5338

European-Non Finnish (NFE)

AF:

0.0000812

AC:

AN:

1096302

Other (OTH)

AF:

0.000541

AC:

AN:

59182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000453

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41562

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0110

AC:

AN:

5184

South Asian (SAS)

AF:

0.00186

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000545

Hom.:

Bravo

AF:

0.000559

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000788

AC:

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Autosomal recessive Parkinson disease 14 (1)

Infantile neuroaxonal dystrophy (1)

not specified (1)

PLA2G6-associated neurodegeneration (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Benign

0.040

Eigen_PC

Benign

-0.015

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0078

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.8

PhyloP100

2.4

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.5

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.21

MVP

0.79

MPC

0.91

ClinPred

0.081

GERP RS

3.3

Varity_R

0.097

gMVP

0.35

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

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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

Computational scores

Splicing

Publications

Other links and lift over