Genetic Variant NM_003712.4:c.721T>C (chr19-281534-A-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_003712.4(PLPP2):c.721T>C(p.Cys241Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,492,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

PLPP2
NM_003712.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.40

Variant links:

Genes affected

PLPP2 (HGNC:9230): (phospholipid phosphatase 2) The protein encoded by this gene is a member of the phosphatidic acid phosphatase (PAP) family. PAPs convert phosphatidic acid to diacylglycerol, and function in de novo synthesis of glycerolipids as well as in receptor-activated signal transduction mediated by phospholipase D. This protein is similar to phosphatidic acid phosphatase type 2A (PPAP2A) and type 2B (PPAP2B). All three proteins contain 6 transmembrane regions, and a consensus N-glycosylation site. This protein has been shown to possess membrane associated PAP activity. Three alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

PLPP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009328842).

BP6

Variant 19-281534-A-G is Benign according to our data. Variant chr19-281534-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3051983.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLPP2	NM_003712.4 link	c.721T>C	p.Cys241Arg	missense_variant	Exon 6 of 6	ENST00000434325.7	NP_003703.1	O43688-1
PLPP2	NM_177543.3 link	c.784T>C	p.Cys262Arg	missense_variant	Exon 6 of 6		NP_808211.1	O43688-2
PLPP2	NM_177526.3 link	c.553T>C	p.Cys185Arg	missense_variant	Exon 6 of 6		NP_803545.1	O43688-3
PLPP2	XM_011528396.3 link	c.739T>C	p.Cys247Arg	missense_variant	Exon 6 of 6		XP_011526698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLPP2	ENST00000434325.7 link	c.721T>C	p.Cys241Arg	missense_variant	Exon 6 of 6	1	NM_003712.4	ENSP00000388565.2		O43688-1

Frequencies

GnomAD3 genomes

AF:

0.00111

AC:

169

AN:

151898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00392

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000326

AC:

AN:

174898

Hom.:

AF XY:

0.000193

AC XY:

AN XY:

93428

show subpopulations

Gnomad AFR exome

AF:

0.00401

Gnomad AMR exome

AF:

0.0000948

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:

0.0000761

AC:

102

AN:

1340362

Hom.:

Cov.:

AF XY:

0.0000607

AC XY:

AN XY:

658814

show subpopulations

Gnomad4 AFR exome

AF:

0.00287

Gnomad4 AMR exome

AF:

0.000196

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:

9.53e-7

Gnomad4 OTH exome

AF:

0.000184

GnomAD4 genome

AF:

0.00111

AC:

169

AN:

152016

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.00391

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000690

Hom.:

Bravo

AF:

0.00110

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000306

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PLPP2-related disorder

Benign:1

May 25, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.50

CADD

Benign

8.6

DANN

Benign

0.72

DEOGEN2

Benign

0.33

.;T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.023

T;T;T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.0093

T;T;T;T

MetaSVM

Benign

-0.88

PrimateAI

Benign

0.47

PROVEAN

Benign

2.3

N;.;.;.

REVEL

Benign

0.17

Sift

Benign

0.44

T;.;.;.

Sift4G

Benign

0.35

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.10

MVP

0.13

MPC

0.57

ClinPred

0.0052

GERP RS

0.22

Varity_R

0.17

gMVP

0.45

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

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