rs138683183

Variant names:

• chr22-38112242-G-A
• rs138683183
• NM_003560.4:c.2340C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003560.4(PLA2G6):​c.2340C>T​(p.Asn780Asn) 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:9
• Conservation: PhyloP100: -0.0180
• Publications: 4 publications found

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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• 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: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 159765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G6	NM_003560.4	MANE Select	c.2340C>T	p.Asn780Asn	synonymous	Exon 17 of 17	NP_003551.2
	PLA2G6	NM_001349864.2		c.2340C>T	p.Asn780Asn	synonymous	Exon 17 of 17	NP_001336793.1	O60733-1
	PLA2G6	NM_001004426.3		c.2178C>T	p.Asn726Asn	synonymous	Exon 16 of 16	NP_001004426.1	O60733-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G6	ENST00000332509.8	TSL:1 MANE Select	c.2340C>T	p.Asn780Asn	synonymous	Exon 17 of 17	ENSP00000333142.3	O60733-1
	PLA2G6	ENST00000402064.5	TSL:1	c.2178C>T	p.Asn726Asn	synonymous	Exon 16 of 16	ENSP00000386100.1	O60733-2
	PLA2G6	ENST00000668949.1		c.2382C>T	p.Asn794Asn	synonymous	Exon 17 of 17	ENSP00000499711.1	A0A590UK51

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

GnomAD2 exomes AF: 0.00752 AC: 1874 AN: 249130 AF XY: 0.00753

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 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

African (AFR) AF: 0.000717 AC: 24 AN: 33470

American (AMR) AF: 0.00368 AC: 164 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 54 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86098

European-Finnish (FIN) AF: 0.0368 AC: 1957 AN: 53228

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.00624 AC: 6938 AN: 1111652

Other (OTH) AF: 0.00638 AC: 385 AN: 60366

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

African (AFR) AF: 0.00101 AC: 42 AN: 41396

American (AMR) AF: 0.00590 AC: 90 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.0409 AC: 434 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00613 AC: 416 AN: 67848

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00434 Hom.: 1

Bravo AF: 0.00413

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00486

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Infantile neuroaxonal dystrophy (1)
-	-	1	PLA2G6-associated neurodegeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.2
DANN	Benign	0.89
PhyloP100		-0.018
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs138683183; hg19: chr22-38508249;