rs138683183

chr22-38112242-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003560.4(PLA2G6):c.2340C>T(p.Asn780=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00653 in 1,612,814 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (64 hom.)
• Consequence: PLA2G6 NM_003560.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0180

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=-0.54).
• BP6: Variant 22-38112242-G-A is Benign according to our data. Variant chr22-38112242-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 159765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38112242-G-A is described in Lovd as [Likely_benign]. Variant chr22-38112242-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.018 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00663 (1006/151848) while in subpopulation NFE AF= 0.00613 (416/67848). AF 95% confidence interval is 0.00564. There are 7 homozygotes in gnomad4. There are 590 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLA2G6	NM_003560.4	c.2340C>T	p.Asn780=	synonymous_variant	17/17	ENST00000332509.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G6	ENST00000332509.8	c.2340C>T	p.Asn780=	synonymous_variant	17/17	1	NM_003560.4	P3

Frequencies

GnomAD3 genomes AF: 0.00662 AC: 1005 AN: 151730 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00591

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0409

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00612

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00752 AC: 1874 AN: 249130 Hom.: 22 AF XY: 0.00753 AC XY: 1016 AN XY: 134990

Gnomad AFR exome AF: 0.00100

Gnomad AMR exome AF: 0.00302

Gnomad ASJ exome AF: 0.00210

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0396

Gnomad NFE exome AF: 0.00740

Gnomad OTH exome AF: 0.00807

GnomAD4 exome AF: 0.00652 AC: 9531 AN: 1460966 Hom.: 64 Cov.: 32 AF XY: 0.00627 AC XY: 4557 AN XY: 726718

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00368

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000697

Gnomad4 FIN exome AF: 0.0368

Gnomad4 NFE exome AF: 0.00624

Gnomad4 OTH exome AF: 0.00638

GnomAD4 genome AF: 0.00663 AC: 1006 AN: 151848 Hom.: 7 Cov.: 32 AF XY: 0.00795 AC XY: 590 AN XY: 74214

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00590

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0409

Gnomad4 NFE AF: 0.00613

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00531 Hom.: 1

Bravo AF: 0.00413

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00486

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

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	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2019	This variant is associated with the following publications: (PMID: 21812034) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PLA2G6: BP4, BP7 -

Infantile neuroaxonal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

PLA2G6-associated neurodegeneration Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	8.2
Dann	Benign	0.89

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: rs138683183; hg19: chr22-38508249;