chr1-19978381-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BS2

The NM_001395463.1(PLA2G2A):​c.184C>T​(p.Arg62Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,459,794 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). 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: 0.000017 (0 hom.)
• Consequence: PLA2G2A NM_001395463.1 missense, splice_region
• Scores: Splicing: ADA: 0.0001745
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.99
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a mutagenesis_site No effect on integrin binding. (size 0) in uniprot entity PA2GA_HUMAN
• BS2: High AC in GnomAdExome4 at 25 AD gene.

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>T	p.Arg62Cys	missense splice_region	Exon 3 of 5	NP_001382392.1	P14555
	PLA2G2A	NM_000300.4		c.184C>T	p.Arg62Cys	missense splice_region	Exon 4 of 6	NP_000291.1	P14555
	PLA2G2A	NM_001161727.2		c.184C>T	p.Arg62Cys	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>T	p.Arg62Cys	missense splice_region	Exon 3 of 5	ENSP00000504762.1	P14555
	PLA2G2A	ENST00000375111.7	TSL:1	c.184C>T	p.Arg62Cys	missense splice_region	Exon 4 of 6	ENSP00000364252.3	P14555
	PLA2G2A	ENST00000400520.8	TSL:1	c.184C>T	p.Arg62Cys	missense splice_region	Exon 3 of 5	ENSP00000383364.3	P14555

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 250118 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1459794 Hom.: 0 Cov.: 35 AF XY: 0.0000248 AC XY: 18 AN XY: 726226

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

American (AMR) AF: 0.0000224 AC: 1 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: 0.000209 AC: 18 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: 0.00000450 AC: 5 AN: 1111590

Other (OTH) AF: 0.0000166 AC: 1 AN: 60286

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.49
DANN	Benign	0.96
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		-5.0
PrimateAI	Benign	0.19	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.22
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.014	D
Polyphen		0.76	P
Vest4		0.48
MutPred		0.76		Loss of helix (P = 0.0558)
MVP		0.37
MPC		1.7
ClinPred		0.47	T
GERP RS		-10
Varity_R		0.18
gMVP		0.78
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.27
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: rs765431164; hg19: chr1-20304874; COSMIC: COSV64287014;