Genetic Variant ENTPD2:p.Leu409Arg (chr9-137048999-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_203468.3(ENTPD2):c.1226T>G(p.Leu409Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,276 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L409P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

ENTPD2
NM_203468.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.41

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTPD2	NM_203468.3 link	c.1226T>G	p.Leu409Arg	missense_variant	Exon 8 of 9	ENST00000355097.7	NP_982293.1	Q9Y5L3-1
ENTPD2	NM_001246.4 link	c.1157T>G	p.Leu386Arg	missense_variant	Exon 8 of 9		NP_001237.1	Q9Y5L3-2
ENTPD2	XM_011519212.3 link	c.917T>G	p.Leu306Arg	missense_variant	Exon 7 of 8		XP_011517514.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENTPD2	ENST00000355097.7 link	c.1226T>G	p.Leu409Arg	missense_variant	Exon 8 of 9	1	NM_203468.3	ENSP00000347213.2	Q9Y5L3-1
ENTPD2	ENST00000312665.7 link	c.1157T>G	p.Leu386Arg	missense_variant	Exon 8 of 9	1		ENSP00000312494.5	Q9Y5L3-2
ENTPD2	ENST00000460614.1 link	n.615T>G		non_coding_transcript_exon_variant	Exon 1 of 2	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.22e-7

AC:

AN:

1385276

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

683494

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31262

American (AMR)

AF:

0.00

AC:

AN:

35484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25050

East Asian (EAS)

AF:

0.00

AC:

AN:

35480

South Asian (SAS)

AF:

0.00

AC:

AN:

79154

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38274

Middle Eastern (MID)

AF:

0.000179

AC:

AN:

5588

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077254

Other (OTH)

AF:

0.00

AC:

AN:

57730

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.

Eigen

Uncertain

0.41

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.85

T;T

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Benign

-0.30

MutationAssessor

Pathogenic

3.8

H;.

PhyloP100

2.4

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.99

D;D

Vest4

0.90

MutPred

0.92

Gain of methylation at L409 (P = 0.0169);.;

MVP

0.70

MPC

0.39

ClinPred

0.98

GERP RS

3.5

Varity_R

0.89

gMVP

0.97

Mutation Taster

=60/40

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over