rs1378888522

Variant names:

• chr8-119564836-C-A
• rs1378888522
• NM_001040092.3:c.2251G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-119564836-C-A
• chr8-119564836-C-T

Variant summary

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

The NM_001040092.3(ENPP2):​c.2251G>T​(p.Asp751Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D751N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENPP2 NM_001040092.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• 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.2251G>T	p.Asp751Tyr	missense	Exon 23 of 25	NP_001035181.1	Q13822-1
	ENPP2	NM_006209.5		c.2407G>T	p.Asp803Tyr	missense	Exon 24 of 26	NP_006200.3
	ENPP2	NM_001130863.3		c.2326G>T	p.Asp776Tyr	missense	Exon 24 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.2251G>T	p.Asp751Tyr	missense	Exon 23 of 25	ENSP00000075322.6	Q13822-1
	ENPP2	ENST00000259486.10	TSL:1	c.2407G>T	p.Asp803Tyr	missense	Exon 24 of 26	ENSP00000259486.6	Q13822-2
	ENPP2	ENST00000522826.5	TSL:1	c.2326G>T	p.Asp776Tyr	missense	Exon 24 of 26	ENSP00000428291.1	Q13822-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.9
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.94	P
Vest4		0.55
MutPred		0.58		Loss of disorder (P = 0.0218)
MVP		0.90
MPC		0.64
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.77
gMVP		0.71
Mutation Taster		=38/62	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: rs1378888522; hg19: chr8-120577076; COSMIC: COSV50045657;