Genetic Variant PLA2G2C:p.Cys142Tyr (chr1-20164016-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001367969.2(PLA2G2C):c.425G>A(p.Cys142Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PLA2G2C
NM_001367969.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.22

Variant links:

Genes affected

PLA2G2C (HGNC:9032): (phospholipase A2 group IIC) Predicted to enable calcium ion binding activity; calcium-dependent phospholipase A2 activity; and phospholipid binding activity. Predicted to be involved in phospholipid metabolic process. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

PLA2G2C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PLA2G2C	NM_001367969.2 link	c.425G>A	p.Cys142Tyr	missense_variant	Exon 5 of 5	ENST00000679259.1	NP_001354898.1
PLA2G2C	NM_001316722.3 link	c.416+3G>A		splice_region_variant, intron_variant	Intron 5 of 5		NP_001303651.1
PLA2G2C	XM_047420216.1 link	c.413+3G>A		splice_region_variant, intron_variant	Intron 2 of 2		XP_047276172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PLA2G2C	ENST00000679259.1 link	c.425G>A	p.Cys142Tyr	missense_variant	Exon 5 of 5		NM_001367969.2	ENSP00000504292.1	Q5R387
PLA2G2C	ENST00000247992.5 link	c.428G>A	p.Cys143Tyr	missense_variant	Exon 3 of 3	5		ENSP00000247992.5	J3KMZ3
PLA2G2C	ENST00000429261.2 link	c.425G>A	p.Cys142Tyr	missense_variant	Exon 4 of 4	5		ENSP00000389335.2	Q5R387
PLA2G2C	ENST00000495760.2 link	n.164-720G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247620

Hom.:

AF XY:

0.00000745

AC XY:

AN XY:

134302

show subpopulations

Gnomad AFR exome

AF:

0.0000654

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000753

AC:

AN:

1461000

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726694

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.428G>A (p.C143Y) alteration is located in exon 3 (coding exon 3) of the PLA2G2C gene. This alteration results from a G to A substitution at nucleotide position 428, causing the cysteine (C) at amino acid position 143 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.32

T;.

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.026

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.59

T;T

M_CAP

Benign

0.043

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Benign

-0.64

MutationAssessor

Pathogenic

4.2

H;.

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-7.9

D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.45

MutPred

0.96

Gain of MoRF binding (P = 0.0683);.;

MVP

0.38

MPC

0.36

ClinPred

1.0

GERP RS

4.4

Varity_R

0.87

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over