22-38143219-C-G

Variant names:

• chr22-38143219-C-G
• rs150190277
• NM_003560.4:c.495G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001349868.2(PLA2G6):​c.5G>C​(p.Gly2Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,614,166 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/7 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. G2V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (3 hom.)
• Consequence: PLA2G6 NM_001349868.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0300
• Publications: 19 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)

ENSG00000279080 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.06).
• BP6: Variant 22-38143219-C-G is Benign according to our data. Variant chr22-38143219-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159771.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00355 (540/152304) while in subpopulation AFR AF = 0.012 (500/41554). AF 95% confidence interval is 0.0112. There are 3 homozygotes in GnomAd4. There are 244 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349868.2. 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.495G>C	p.Gly165Gly	synonymous	Exon 4 of 17	NP_003551.2
	PLA2G6	NM_001349868.2		c.5G>C	p.Gly2Ala	missense	Exon 4 of 16	NP_001336797.1
	PLA2G6	NM_001349864.2		c.495G>C	p.Gly165Gly	synonymous	Exon 4 of 17	NP_001336793.1	O60733-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G6	ENST00000332509.8	TSL:1 MANE Select	c.495G>C	p.Gly165Gly	synonymous	Exon 4 of 17	ENSP00000333142.3	O60733-1
	PLA2G6	ENST00000402064.5	TSL:1	c.495G>C	p.Gly165Gly	synonymous	Exon 4 of 16	ENSP00000386100.1	O60733-2
	PLA2G6	ENST00000668949.1		c.495G>C	p.Gly165Gly	synonymous	Exon 4 of 17	ENSP00000499711.1	A0A590UK51

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 536 AN: 152186 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000927 AC: 233 AN: 251466 AF XY: 0.000677

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000428 AC: 625 AN: 1461862 Hom.: 3 Cov.: 33 AF XY: 0.000371 AC XY: 270 AN XY: 727234

African (AFR) AF: 0.0119 AC: 398 AN: 33478

American (AMR) AF: 0.000872 AC: 39 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000112 AC: 124 AN: 1111996

Other (OTH) AF: 0.000994 AC: 60 AN: 60390

GnomAD4 genome AF: 0.00355 AC: 540 AN: 152304 Hom.: 3 Cov.: 32 AF XY: 0.00328 AC XY: 244 AN XY: 74476

African (AFR) AF: 0.0120 AC: 500 AN: 41554

American (AMR) AF: 0.00131 AC: 20 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68028

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000962 Hom.: 0

Bravo AF: 0.00392

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Infantile neuroaxonal dystrophy (1)
-	1	-	Iron accumulation in brain (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.9
DANN	Benign	0.95
PhyloP100		-0.030
PromoterAI		0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	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: rs150190277; hg19: chr22-38539226;