chr19-281534-A-G

Variant names:

• chr19-281534-A-G
• rs61738956
• NM_003712.4:c.721T>C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

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
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.40

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]

ACMG classification

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	c.721T>C	p.Cys241Arg	missense_variant	Exon 6 of 6	ENST00000434325.7	NP_003703.1
PLPP2	NM_177543.3	c.784T>C	p.Cys262Arg	missense_variant	Exon 6 of 6		NP_808211.1
PLPP2	NM_177526.3	c.553T>C	p.Cys185Arg	missense_variant	Exon 6 of 6		NP_803545.1
PLPP2	XM_011528396.3	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	c.721T>C	p.Cys241Arg	missense_variant	Exon 6 of 6	1	NM_003712.4	ENSP00000388565.2

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 151898 Hom.: 0 Cov.: 30

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: 57 AN: 174898 Hom.: 0 AF XY: 0.000193 AC XY: 18 AN XY: 93428

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.: 0 Cov.: 32 AF XY: 0.0000607 AC XY: 40 AN XY: 658814

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.: 0 Cov.: 30 AF XY: 0.00110 AC XY: 82 AN XY: 74298

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.: 0

Bravo AF: 0.00110

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000306 AC: 37

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

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	T
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	N
LIST_S2	Benign	0.023	T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0093	T;T;T;T
MetaSVM	Benign	-0.88	T
PrimateAI	Benign	0.47	T
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	T
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

Other links and lift over

dbSNP: rs61738956; hg19: chr19-281534;