Genetic Variant ENTPD2:p.Leu442Pro (chr9-137048820-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_203468.3(ENTPD2):c.1325T>C(p.Leu442Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,415,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

ENTPD2
NM_203468.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.14

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTPD2	NM_203468.3 link	c.1325T>C	p.Leu442Pro	missense_variant	Exon 9 of 9	ENST00000355097.7	NP_982293.1	Q9Y5L3-1
ENTPD2	NM_001246.4 link	c.1256T>C	p.Leu419Pro	missense_variant	Exon 9 of 9		NP_001237.1	Q9Y5L3-2
ENTPD2	XM_011519212.3 link	c.1016T>C	p.Leu339Pro	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.1325T>C	p.Leu442Pro	missense_variant	Exon 9 of 9	1	NM_203468.3	ENSP00000347213.2	Q9Y5L3-1
ENTPD2	ENST00000312665.7 link	c.1256T>C	p.Leu419Pro	missense_variant	Exon 9 of 9	1		ENSP00000312494.5	Q9Y5L3-2
ENTPD2	ENST00000460614.1 link	n.714T>C		non_coding_transcript_exon_variant	Exon 2 of 2	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000299

AC:

AN:

200470

AF XY:

0.0000184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000332

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000235

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000210

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1415348

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

698990

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32500

American (AMR)

AF:

0.0000489

AC:

AN:

40858

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23038

East Asian (EAS)

AF:

0.000154

AC:

AN:

38870

South Asian (SAS)

AF:

0.00

AC:

AN:

79150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5552

European-Non Finnish (NFE)

AF:

9.19e-7

AC:

AN:

1087958

Other (OTH)

AF:

0.000326

AC:

AN:

58282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000435

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000250

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1325T>C (p.L442P) alteration is located in exon 9 (coding exon 9) of the ENTPD2 gene. This alteration results from a T to C substitution at nucleotide position 1325, causing the leucine (L) at amino acid position 442 to be replaced by a proline (P). 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

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.087

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Benign

-0.59

MutationAssessor

Pathogenic

4.0

H;.

PhyloP100

7.1

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.6

D;D

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.83

MutPred

0.81

Loss of stability (P = 0.0345);.;

MVP

0.85

MPC

0.42

ClinPred

1.0

GERP RS

2.8

Varity_R

0.99

gMVP

0.98

Mutation Taster

=34/66

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr9-137048820-A-G

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