chr22-38112165-G-A

Variant names:

• chr22-38112165-G-A
• rs140758033
• NM_003560.4:c.2417C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003560.4(PLA2G6):​c.2417C>T​(p.Pro806Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,429,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P806R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLA2G6 NM_003560.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.36
• Publications: 0 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16211408).

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.2417C>T	p.Pro806Leu	missense	Exon 17 of 17	NP_003551.2
	PLA2G6	NM_001349864.2		c.2417C>T	p.Pro806Leu	missense	Exon 17 of 17	NP_001336793.1
	PLA2G6	NM_001004426.3		c.2255C>T	p.Pro752Leu	missense	Exon 16 of 16	NP_001004426.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G6	ENST00000332509.8	TSL:1 MANE Select	c.2417C>T	p.Pro806Leu	missense	Exon 17 of 17	ENSP00000333142.3
	PLA2G6	ENST00000402064.5	TSL:1	c.2255C>T	p.Pro752Leu	missense	Exon 16 of 16	ENSP00000386100.1
	PLA2G6	ENST00000668949.1		c.2459C>T	p.Pro820Leu	missense	Exon 17 of 17	ENSP00000499711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1429348 Hom.: 0 Cov.: 31 AF XY: 0.00000282 AC XY: 2 AN XY: 708064

African (AFR) AF: 0.00 AC: 0 AN: 32838

American (AMR) AF: 0.00 AC: 0 AN: 39556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25462

East Asian (EAS) AF: 0.00 AC: 0 AN: 37940

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5338

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096302

Other (OTH) AF: 0.00 AC: 0 AN: 59182

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.10
MutPred		0.42		Gain of helix (P = 0.0082)
MVP		0.65
MPC		0.89
ClinPred		0.91	D
GERP RS		3.3
Varity_R		0.097
gMVP		0.37
Mutation Taster		=94/6	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: rs140758033; hg19: chr22-38508172;