Genetic Variant ENTPD2:p.Pro452Leu (chr9-137048790-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_203468.3(ENTPD2):c.1355C>T(p.Pro452Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000349 in 1,434,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

ENTPD2
NM_203468.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.787

Publications

1 publications found

Variant links:

Genes affected

ENTPD2 (HGNC:3364): (ectonucleoside triphosphate diphosphohydrolase 2) The protein encoded by this gene is the type 2 enzyme of the ecto-nucleoside triphosphate diphosphohydrolase family (E-NTPDase). E-NTPDases are a family of ecto-nucleosidases that hydrolyze 5'-triphosphates. This ecto-ATPase is an integral membrane protein. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ENTPD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.053090006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTPD2	NM_203468.3 link	c.1355C>T	p.Pro452Leu	missense_variant	Exon 9 of 9	ENST00000355097.7	NP_982293.1	Q9Y5L3-1
ENTPD2	NM_001246.4 link	c.1286C>T	p.Pro429Leu	missense_variant	Exon 9 of 9		NP_001237.1	Q9Y5L3-2
ENTPD2	XM_011519212.3 link	c.1046C>T	p.Pro349Leu	missense_variant	Exon 8 of 8		XP_011517514.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENTPD2	ENST00000355097.7 link	c.1355C>T	p.Pro452Leu	missense_variant	Exon 9 of 9	1	NM_203468.3	ENSP00000347213.2	Q9Y5L3-1
ENTPD2	ENST00000312665.7 link	c.1286C>T	p.Pro429Leu	missense_variant	Exon 9 of 9	1		ENSP00000312494.5	Q9Y5L3-2
ENTPD2	ENST00000460614.1 link	n.744C>T		non_coding_transcript_exon_variant	Exon 2 of 2	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

216958

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000349

AC:

AN:

1434450

Hom.:

Cov.:

AF XY:

0.00000422

AC XY:

AN XY:

710806

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33076

American (AMR)

AF:

0.00

AC:

AN:

42962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24336

East Asian (EAS)

AF:

0.00

AC:

AN:

39244

South Asian (SAS)

AF:

0.00

AC:

AN:

82082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.00000455

AC:

AN:

1097856

Other (OTH)

AF:

0.00

AC:

AN:

59172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 26, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1355C>T (p.P452L) alteration is located in exon 9 (coding exon 9) of the ENTPD2 gene. This alteration results from a C to T substitution at nucleotide position 1355, causing the proline (P) at amino acid position 452 to be replaced by a leucine (L). 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

Benign

0.072

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.048

T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.46

N;.

PhyloP100

-0.79

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.047

Sift

Benign

0.34

T;T

Sift4G

Benign

0.29

T;T

Polyphen

0.0050

B;B

Vest4

0.083

MutPred

0.48

Loss of disorder (P = 0.0149);.;

MVP

0.36

MPC

0.057

ClinPred

0.082

GERP RS

0.99

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.052

gMVP

0.50

Mutation Taster

=98/2

polymorphism

(source)

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

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9-137048790-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over