1-19978381-G-C

Variant names:

• chr1-19978381-G-C
• rs765431164
• NM_001395463.1:c.184C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001395463.1(PLA2G2A):​c.184C>G​(p.Arg62Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R62H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PLA2G2A NM_001395463.1 missense, splice_region
• Scores: Splicing: ADA: 0.002453
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.99
• Publications: 0 publications found

Genes affected

PLA2G2A (HGNC:9031): (phospholipase A2 group IIA) The protein encoded by this gene is a member of the phospholipase A2 family (PLA2). PLA2s constitute a diverse family of enzymes with respect to sequence, function, localization, and divalent cation requirements. This gene product belongs to group II, which contains secreted form of PLA2, an extracellular enzyme that has a low molecular mass and requires calcium ions for catalysis. It catalyzes the hydrolysis of the sn-2 fatty acid acyl ester bond of phosphoglycerides, releasing free fatty acids and lysophospholipids, and thought to participate in the regulation of the phospholipid metabolism in biomembranes. Several alternatively spliced transcript variants with different 5' UTRs have been found for this gene.[provided by RefSeq, Sep 2009]

PLA2G2A Gene-Disease associations (from GenCC):

• colorectal cancer

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a mutagenesis_site No effect on integrin binding. (size 0) in uniprot entity PA2GA_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395463.1. 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
	PLA2G2A	NM_001395463.1	MANE Select	c.184C>G	p.Arg62Gly	missense splice_region	Exon 3 of 5	NP_001382392.1	P14555
	PLA2G2A	NM_000300.4		c.184C>G	p.Arg62Gly	missense splice_region	Exon 4 of 6	NP_000291.1	P14555
	PLA2G2A	NM_001161727.2		c.184C>G	p.Arg62Gly	missense splice_region	Exon 4 of 6	NP_001155199.1	P14555

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G2A	ENST00000482011.3	TSL:1 MANE Select	c.184C>G	p.Arg62Gly	missense splice_region	Exon 3 of 5	ENSP00000504762.1	P14555
	PLA2G2A	ENST00000375111.7	TSL:1	c.184C>G	p.Arg62Gly	missense splice_region	Exon 4 of 6	ENSP00000364252.3	P14555
	PLA2G2A	ENST00000400520.8	TSL:1	c.184C>G	p.Arg62Gly	missense splice_region	Exon 3 of 5	ENSP00000383364.3	P14555

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459794 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 726226

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5096

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111590

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.012
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0060	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		-5.0
PrimateAI	Benign	0.18	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.20
Sift	Benign	0.10	T
Sift4G	Benign	0.10	T
Polyphen		0.98	D
Vest4		0.46
MutPred		0.79		Loss of phosphorylation at T60 (P = 0.1283)
MVP		0.44
MPC		1.6
ClinPred		0.86	D
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.83
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0025
dbscSNV1_RF	Benign	0.33
SpliceAI score (max)		0.010		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: rs765431164; hg19: chr1-20304874;