19-281534-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C241G) has been classified as Uncertain significance.

• 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 criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.40
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• 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 VariationId is 3051983.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003712.4. 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
	PLPP2	NM_003712.4	MANE Select	c.721T>C	p.Cys241Arg	missense	Exon 6 of 6	NP_003703.1	O43688-1
	PLPP2	NM_177543.3		c.784T>C	p.Cys262Arg	missense	Exon 6 of 6	NP_808211.1	O43688-2
	PLPP2	NM_177526.3		c.553T>C	p.Cys185Arg	missense	Exon 6 of 6	NP_803545.1	O43688-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLPP2	ENST00000434325.7	TSL:1 MANE Select	c.721T>C	p.Cys241Arg	missense	Exon 6 of 6	ENSP00000388565.2	O43688-1
	PLPP2	ENST00000327790.7	TSL:5	c.784T>C	p.Cys262Arg	missense	Exon 6 of 6	ENSP00000329697.1	O43688-2
	PLPP2	ENST00000951587.1		c.721T>C	p.Cys241Arg	missense	Exon 6 of 7	ENSP00000621646.1

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

GnomAD2 exomes AF: 0.000326 AC: 57 AN: 174898 AF XY: 0.000193

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 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

African (AFR) AF: 0.00287 AC: 85 AN: 29596

American (AMR) AF: 0.000196 AC: 6 AN: 30638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20336

East Asian (EAS) AF: 0.00 AC: 0 AN: 35584

South Asian (SAS) AF: 0.00 AC: 0 AN: 65434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5224

European-Non Finnish (NFE) AF: 9.53e-7 AC: 1 AN: 1049546

Other (OTH) AF: 0.000184 AC: 10 AN: 54418

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152016 Hom.: 0 Cov.: 30 AF XY: 0.00110 AC XY: 82 AN XY: 74298

African (AFR) AF: 0.00391 AC: 162 AN: 41460

American (AMR) AF: 0.000459 AC: 7 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000526 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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	PLPP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.88	T
PhyloP100		1.4
PrimateAI	Benign	0.47	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.17
Sift	Benign	0.44	T
Sift4G	Benign	0.35	T
Polyphen		0.0	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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs61738956; hg19: chr19-281534;