17-4809346-C-G

Variant names:

• chr17-4809346-C-G
• rs138074240
• NM_002663.5:c.538C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002663.5(PLD2):​c.538C>G​(p.Arg180Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R180H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLD2 NM_002663.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.76
• Publications: 4 publications found

Genes affected

PLD2 (HGNC:9068): (phospholipase D2) The protein encoded by this gene catalyzes the hydrolysis of phosphatidylcholine to phosphatidic acid and choline. The activity of the encoded enzyme is enhanced by phosphatidylinositol 4,5-bisphosphate and ADP-ribosylation factor-1. This protein localizes to the peripheral membrane and may be involved in cytoskeletal organization, cell cycle control, transcriptional regulation, and/or regulated secretion. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002663.5. 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
	PLD2	NM_002663.5	MANE Select	c.538C>G	p.Arg180Gly	missense	Exon 6 of 25	NP_002654.3
	PLD2	NM_001243108.2		c.538C>G	p.Arg180Gly	missense	Exon 6 of 25	NP_001230037.1	O14939-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLD2	ENST00000263088.11	TSL:1 MANE Select	c.538C>G	p.Arg180Gly	missense	Exon 6 of 25	ENSP00000263088.5	O14939-1
	PLD2	ENST00000572940.5	TSL:1	c.538C>G	p.Arg180Gly	missense	Exon 6 of 25	ENSP00000459571.1	O14939-4
	PLD2	ENST00000964340.1		c.595C>G	p.Arg199Gly	missense	Exon 6 of 25	ENSP00000634399.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.63		Loss of stability (P = 0.019)
MVP		0.69
MPC		0.69
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.66
gMVP		0.66

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: rs138074240; hg19: chr17-4712641;