rs115371819

Variant names:

• chr6-131879936-G-A
• rs115371819
• NM_006208.3:c.2002G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006208.3(ENPP1):​c.2002G>A​(p.Glu668Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,613,632 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (53 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (41 hom.)
• Consequence: ENPP1 NM_006208.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.77
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022817552).
• BP6: Variant 6-131879936-G-A is Benign according to our data. Variant chr6-131879936-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 161094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0139 (2108/152186) while in subpopulation AFR AF = 0.0485 (2015/41518). AF 95% confidence interval is 0.0468. There are 53 homozygotes in GnomAd4. There are 993 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 53 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.2002G>A	p.Glu668Lys	missense	Exon 20 of 25	NP_006199.2	P22413

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPP1	ENST00000647893.1	MANE Select	c.2002G>A	p.Glu668Lys	missense	Exon 20 of 25	ENSP00000498074.1	P22413
	ENPP1	ENST00000922186.1		c.1870G>A	p.Glu624Lys	missense	Exon 19 of 24	ENSP00000592245.1
	ENPP1	ENST00000513998.5	TSL:5	n.*839G>A		non_coding_transcript_exon	Exon 20 of 25	ENSP00000422424.1	E9PE72

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2102 AN: 152068 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00407

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00344 AC: 865 AN: 251352 AF XY: 0.00254

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00143 AC: 2094 AN: 1461446 Hom.: 41 Cov.: 30 AF XY: 0.00125 AC XY: 906 AN XY: 727070

African (AFR) AF: 0.0510 AC: 1707 AN: 33464

American (AMR) AF: 0.00210 AC: 94 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000122 AC: 136 AN: 1111620

Other (OTH) AF: 0.00245 AC: 148 AN: 60374

GnomAD4 genome AF: 0.0139 AC: 2108 AN: 152186 Hom.: 53 Cov.: 32 AF XY: 0.0133 AC XY: 993 AN XY: 74424

African (AFR) AF: 0.0485 AC: 2015 AN: 41518

American (AMR) AF: 0.00406 AC: 62 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68010

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00534 Hom.: 34

Bravo AF: 0.0149

ESP6500AA AF: 0.0422 AC: 186

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00432 AC: 525

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Arterial calcification, generalized, of infancy, 1 (2)
-	-	1	Hypophosphatemic rickets, autosomal recessive, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	3.3
DANN	Benign	0.40
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.77	N
PhyloP100		1.8
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.095
Sift	Benign	0.48	T
Sift4G	Benign	0.84	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.54
MPC		0.23
ClinPred		0.0026	T
GERP RS		4.4
Varity_R		0.019
gMVP		0.44
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs115371819; hg19: chr6-132201076; COSMIC: COSV62934452; COSMIC: COSV62934452;