8-119582495-G-C

Variant names:

• chr8-119582495-G-C
• rs753500207
• NM_001040092.3:c.1651C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001040092.3(ENPP2):​c.1651C>G​(p.Pro551Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ENPP2 NM_001040092.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60
• Publications: 0 publications found

Genes affected

ENPP2 (HGNC:3357): (ectonucleotide pyrophosphatase/phosphodiesterase 2) The protein encoded by this gene functions as both a phosphodiesterase, which cleaves phosphodiester bonds at the 5' end of oligonucleotides, and a phospholipase, which catalyzes production of lysophosphatidic acid (LPA) in extracellular fluids. LPA evokes growth factor-like responses including stimulation of cell proliferation and chemotaxis. This gene product stimulates the motility of tumor cells and has angiogenic properties, and its expression is upregulated in several kinds of carcinomas. The gene product is secreted and further processed to make the biologically active form. Several alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040092.3. 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
	ENPP2	NM_001040092.3	MANE Select	c.1651C>G	p.Pro551Ala	missense	Exon 18 of 25	NP_001035181.1	Q13822-1
	ENPP2	NM_006209.5		c.1807C>G	p.Pro603Ala	missense	Exon 19 of 26	NP_006200.3
	ENPP2	NM_001130863.3		c.1651C>G	p.Pro551Ala	missense	Exon 18 of 26	NP_001124335.1	Q13822-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPP2	ENST00000075322.11	TSL:1 MANE Select	c.1651C>G	p.Pro551Ala	missense	Exon 18 of 25	ENSP00000075322.6	Q13822-1
	ENPP2	ENST00000259486.10	TSL:1	c.1807C>G	p.Pro603Ala	missense	Exon 19 of 26	ENSP00000259486.6	Q13822-2
	ENPP2	ENST00000522826.5	TSL:1	c.1651C>G	p.Pro551Ala	missense	Exon 18 of 26	ENSP00000428291.1	Q13822-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461722 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111864

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.089	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.098	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.45
Sift	Benign	0.048	D
Sift4G	Benign	0.065	T
Polyphen		1.0	D
Vest4		0.65
MutPred		0.47		Loss of sheet (P = 0.0126)
MVP		0.85
MPC		0.79
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.80
gMVP		0.70
Mutation Taster		=23/77	disease causing

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: rs753500207; hg19: chr8-120594735;