6-131884939-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006208.3(ENPP1):c.2320C>T(p.Arg774Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,613,628 control chromosomes in the GnomAD database, including 1,228 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R774H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.028 ( 108 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1120 hom. )

Consequence

ENPP1
NM_006208.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7O:1

Conservation

PhyloP100: 1.82

Publications

30 publications found

Variant links:

Genes affected

ENPP1 (HGNC:3356): (ectonucleotide pyrophosphatase/phosphodiesterase 1) This gene is a member of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family. The encoded protein is a type II transmembrane glycoprotein comprising two identical disulfide-bonded subunits. This protein has broad specificity and cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. This protein may function to hydrolyze nucleoside 5' triphosphates to their corresponding monophosphates and may also hydrolyze diadenosine polyphosphates. Mutations in this gene have been associated with 'idiopathic' infantile arterial calcification, ossification of the posterior longitudinal ligament of the spine (OPLL), and insulin resistance. [provided by RefSeq, Jul 2008]

ENPP1 Gene-Disease associations (from GenCC):

arterial calcification, generalized, of infancy, 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
hypopigmentation-punctate palmoplantar keratoderma syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
hypophosphatemic rickets, autosomal recessive, 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
arterial calcification of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive hypophosphatemic rickets
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive inherited pseudoxanthoma elasticum
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENPP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044817626).

BP6

Variant 6-131884939-C-T is Benign according to our data. Variant chr6-131884939-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13586.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0282 (4298/152234) while in subpopulation NFE AF = 0.0366 (2491/68020). AF 95% confidence interval is 0.0354. There are 108 homozygotes in GnomAd4. There are 2250 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 108 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006208.3. 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
	ENPP1	NM_006208.3	MANE Select	c.2320C>T	p.Arg774Cys	missense	Exon 23 of 25	NP_006199.2	P22413

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ENPP1	ENST00000647893.1	MANE Select	c.2320C>T	p.Arg774Cys	missense	Exon 23 of 25	ENSP00000498074.1	P22413
ENPP1	ENST00000922186.1		c.2188C>T	p.Arg730Cys	missense	Exon 22 of 24	ENSP00000592245.1
ENPP1	ENST00000513998.5	TSL:5	n.*1157C>T		non_coding_transcript_exon	Exon 23 of 25	ENSP00000422424.1	E9PE72

Frequencies

GnomAD3 genomes

AF:

0.0283

AC:

4300

AN:

152116

Hom.:

109

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00558

Gnomad AMI

AF:

0.0987

Gnomad AMR

AF:

0.0146

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0357

Gnomad FIN

AF:

0.0925

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0366

Gnomad OTH

AF:

0.0311

GnomAD2 exomes

AF:

0.0331

AC:

8311

AN:

251400

AF XY:

0.0345

show subpopulations

Gnomad AFR exome

AF:

0.00511

Gnomad AMR exome

AF:

0.0108

Gnomad ASJ exome

AF:

0.0142

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0973

Gnomad NFE exome

AF:

0.0367

Gnomad OTH exome

AF:

0.0336

GnomAD4 exome

AF:

0.0344

AC:

50339

AN:

1461394

Hom.:

1120

Cov.:

AF XY:

0.0349

AC XY:

25405

AN XY:

727026

show subpopulations

African (AFR)

AF:

0.00460

AC:

154

AN:

33480

American (AMR)

AF:

0.0119

AC:

532

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0134

AC:

351

AN:

26128

East Asian (EAS)

AF:

0.000227

AC:

AN:

39684

South Asian (SAS)

AF:

0.0402

AC:

3468

AN:

86250

European-Finnish (FIN)

AF:

0.0971

AC:

5186

AN:

53418

Middle Eastern (MID)

AF:

0.0248

AC:

143

AN:

5768

European-Non Finnish (NFE)

AF:

0.0347

AC:

38570

AN:

1111564

Other (OTH)

AF:

0.0319

AC:

1926

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

2558

5116

7675

10233

12791

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1434

2868

4302

5736

7170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0282

AC:

4298

AN:

152234

Hom.:

108

Cov.:

AF XY:

0.0302

AC XY:

2250

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00556

AC:

231

AN:

41550

American (AMR)

AF:

0.0147

AC:

224

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3468

East Asian (EAS)

AF:

0.000579

AC:

AN:

5182

South Asian (SAS)

AF:

0.0355

AC:

171

AN:

4820

European-Finnish (FIN)

AF:

0.0925

AC:

980

AN:

10592

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0366

AC:

2491

AN:

68020

Other (OTH)

AF:

0.0308

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

218

435

653

870

1088

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0312

Hom.:

279

Bravo

AF:

0.0212

TwinsUK

AF:

0.0313

AC:

116

ALSPAC

AF:

0.0335

AC:

129

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.0365

AC:

314

ExAC

AF:

0.0332

AC:

4028

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Arterial calcification, generalized, of infancy, 1 (3)

not provided (2)

not specified (2)

Hypophosphatemic rickets, autosomal recessive, 2 (1)

Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Benign

0.027

Eigen_PC

Benign

0.018

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.2

PhyloP100

1.8

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.7

REVEL

Benign

0.26

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.025

Polyphen

0.97

Vest4

0.14

MPC

0.75

ClinPred

0.038

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.070

gMVP

0.55

Mutation Taster

=82/18

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over