rs2413502

Positions:

• chr22-38129554-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003560.4(PLA2G6):​c.1086C>T​(p.Asn362=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,612,058 control chromosomes in the GnomAD database, including 1,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (785 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (674 hom.)
• Consequence: PLA2G6 NM_003560.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0780

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 22-38129554-G-A is Benign according to our data. Variant chr22-38129554-G-A is described in ClinVar as [Benign]. Clinvar id is 159727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38129554-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.078 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLA2G6	NM_003560.4	c.1086C>T	p.Asn362=	synonymous_variant	8/17	ENST00000332509.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G6	ENST00000332509.8	c.1086C>T	p.Asn362=	synonymous_variant	8/17	1	NM_003560.4	P3

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8347 AN: 152126 Hom.: 783 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0239

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.0359

GnomAD3 exomes AF: 0.0150 AC: 3763 AN: 251416 Hom.: 320 AF XY: 0.0111 AC XY: 1513 AN XY: 135908

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.00317

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00634 AC: 9258 AN: 1459814 Hom.: 674 Cov.: 30 AF XY: 0.00561 AC XY: 4077 AN XY: 726396

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.00322

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000534

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00111

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0550 AC: 8371 AN: 152244 Hom.: 785 Cov.: 32 AF XY: 0.0533 AC XY: 3967 AN XY: 74446

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.0239

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00148

Gnomad4 OTH AF: 0.0355

Alfa AF: 0.0118 Hom.: 258

Bravo AF: 0.0618

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2018	- -

Infantile neuroaxonal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

PLA2G6-associated neurodegeneration Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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
BayesDel_noAF	Benign	-0.67
CADD	Benign	8.8
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs2413502; hg19: chr22-38525561;