chr22-38115649-CG-C

Variant names:

• chr22-38115649-CG-C
• rs730882214
• NM_003560.4:c.1911delC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_003560.4(PLA2G6):​c.1911delC​(p.Ser637ArgfsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S637S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLA2G6 NM_003560.4 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.652
• 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, 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-38115649-CG-C is Pathogenic according to our data. Variant chr22-38115649-CG-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 183302.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1911delC	p.Ser637ArgfsTer29	frameshift	Exon 14 of 17	NP_003551.2
	PLA2G6	NM_001349864.2		c.1911delC	p.Ser637ArgfsTer29	frameshift	Exon 14 of 17	NP_001336793.1
	PLA2G6	NM_001004426.3		c.1749delC	p.Ser583ArgfsTer29	frameshift	Exon 13 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.1911delC	p.Ser637ArgfsTer29	frameshift	Exon 14 of 17	ENSP00000333142.3
	PLA2G6	ENST00000402064.5	TSL:1	c.1749delC	p.Ser583ArgfsTer29	frameshift	Exon 13 of 16	ENSP00000386100.1
	PLA2G6	ENST00000668949.1		c.1749delC	p.Ser583ArgfsTer29	frameshift	Exon 13 of 17	ENSP00000499711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodegeneration with brain iron accumulation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.65
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs730882214; hg19: chr22-38511656;