22-38148291-A-G

Variant names:

• chr22-38148291-A-G
• rs2284063
• NM_003560.4:c.210-2638T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003560.4(PLA2G6):​c.210-2638T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 530,902 control chromosomes in the GnomAD database, including 39,957 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.40 (12542 hom., cov: 32)
  • Exomes 𝑓: 0.37 (27415 hom.)
• Consequence: PLA2G6 NM_003560.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 74 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, 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

ENSG00000279080 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G6	NM_003560.4	MANE Select	c.210-2638T>C		intron	N/A	NP_003551.2
	PLA2G6	NM_001349864.2		c.210-2638T>C		intron	N/A	NP_001336793.1
	PLA2G6	NM_001004426.3		c.210-2638T>C		intron	N/A	NP_001004426.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G6	ENST00000332509.8	TSL:1 MANE Select	c.210-2638T>C		intron	N/A	ENSP00000333142.3
	PLA2G6	ENST00000402064.5	TSL:1	c.210-2638T>C		intron	N/A	ENSP00000386100.1
	ENSG00000279080	ENST00000624072.1	TSL:6	n.18076A>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60647 AN: 151930 Hom.: 12520 Cov.: 32

Gnomad AFR AF: 0.487

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.376

GnomAD4 exome AF: 0.374 AC: 141712 AN: 378854 Hom.: 27415 Cov.: 0 AF XY: 0.380 AC XY: 76622 AN XY: 201486

African (AFR) AF: 0.498 AC: 5009 AN: 10054

American (AMR) AF: 0.428 AC: 6113 AN: 14294

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 4408 AN: 11744

East Asian (EAS) AF: 0.266 AC: 6369 AN: 23984

South Asian (SAS) AF: 0.472 AC: 20424 AN: 43260

European-Finnish (FIN) AF: 0.349 AC: 7800 AN: 22348

Middle Eastern (MID) AF: 0.425 AC: 738 AN: 1736

European-Non Finnish (NFE) AF: 0.359 AC: 82481 AN: 229520

Other (OTH) AF: 0.382 AC: 8370 AN: 21914

GnomAD4 genome AF: 0.399 AC: 60727 AN: 152048 Hom.: 12542 Cov.: 32 AF XY: 0.402 AC XY: 29888 AN XY: 74328

African (AFR) AF: 0.487 AC: 20171 AN: 41438

American (AMR) AF: 0.423 AC: 6452 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1253 AN: 3472

East Asian (EAS) AF: 0.259 AC: 1345 AN: 5190

South Asian (SAS) AF: 0.486 AC: 2343 AN: 4824

European-Finnish (FIN) AF: 0.342 AC: 3608 AN: 10564

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.356 AC: 24173 AN: 67976

Other (OTH) AF: 0.381 AC: 807 AN: 2116

Alfa AF: 0.366 Hom.: 41642

Bravo AF: 0.404

Asia WGS AF: 0.429 AC: 1496 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.96
DANN	Benign	0.37
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs2284063; hg19: chr22-38544298;