rs201408221

Variant names:

• chr19-282274-G-A
• rs201408221
• NM_003712.4:c.577C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003712.4(PLPP2):​c.577C>T​(p.Arg193Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,613,708 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: PLPP2 NM_003712.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044211775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLPP2	NM_003712.4	c.577C>T	p.Arg193Trp	missense_variant	Exon 5 of 6	ENST00000434325.7	NP_003703.1
PLPP2	NM_177543.3	c.640C>T	p.Arg214Trp	missense_variant	Exon 5 of 6		NP_808211.1
PLPP2	NM_177526.3	c.409C>T	p.Arg137Trp	missense_variant	Exon 5 of 6		NP_803545.1
PLPP2	XM_011528396.3	c.595C>T	p.Arg199Trp	missense_variant	Exon 5 of 6		XP_011526698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLPP2	ENST00000434325.7	c.577C>T	p.Arg193Trp	missense_variant	Exon 5 of 6	1	NM_003712.4	ENSP00000388565.2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152070 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000231 AC: 58 AN: 251038 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135776

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000153 AC: 224 AN: 1461638 Hom.: 1 Cov.: 32 AF XY: 0.000144 AC XY: 105 AN XY: 727146

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000809

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152070 Hom.: 0 Cov.: 30 AF XY: 0.000162 AC XY: 12 AN XY: 74268

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000309 Hom.: 1

Bravo AF: 0.000170

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.640C>T (p.R214W) alteration is located in exon 5 (coding exon 5) of the PLPP2 gene. This alteration results from a C to T substitution at nucleotide position 640, causing the arginine (R) at amino acid position 214 to be replaced by a tryptophan (W). 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	Uncertain	0.53
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	.;D;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.044	T;T;T;T
MetaSVM	Benign	-0.55	T
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.2	D;.;D;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.026	D;.;D;.
Sift4G	Uncertain	0.026	D;D;D;D
Polyphen		0.46	P;B;.;.
Vest4		0.93
MVP		0.83
MPC		0.38
ClinPred		0.31	T
GERP RS		-0.0063
Varity_R		0.72
gMVP		0.78

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: rs201408221; hg19: chr19-282274; COSMIC: COSV54120671; COSMIC: COSV54120671;