NM_006208.3:c.240+18201G>C

Variant names:

• chr6-131826476-G-C
• rs6917903
• NM_006208.3:c.240+18201G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006208.3(ENPP1):​c.240+18201G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,048,810 control chromosomes in the GnomAD database, including 87,529 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (10862 hom., cov: 33)
  • Exomes 𝑓: 0.41 (76667 hom.)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0310
• Publications: 3 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

ENSG00000237115 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

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.240+18201G>C		intron	N/A	NP_006199.2	P22413

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPP1	ENST00000647893.1	MANE Select	c.240+18201G>C		intron	N/A	ENSP00000498074.1	P22413
	ENPP1	ENST00000922186.1		c.240+18201G>C		intron	N/A	ENSP00000592245.1
	ENSG00000237115	ENST00000455305.1	TSL:6	n.1938C>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56394 AN: 151914 Hom.: 10863 Cov.: 33

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.396

GnomAD4 exome AF: 0.412 AC: 369264 AN: 896778 Hom.: 76667 Cov.: 12 AF XY: 0.412 AC XY: 192623 AN XY: 467078

African (AFR) AF: 0.273 AC: 6093 AN: 22284

American (AMR) AF: 0.322 AC: 13071 AN: 40646

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 8644 AN: 20744

East Asian (EAS) AF: 0.461 AC: 16944 AN: 36772

South Asian (SAS) AF: 0.390 AC: 27290 AN: 70010

European-Finnish (FIN) AF: 0.351 AC: 17686 AN: 50386

Middle Eastern (MID) AF: 0.404 AC: 1813 AN: 4486

European-Non Finnish (NFE) AF: 0.428 AC: 261319 AN: 610628

Other (OTH) AF: 0.402 AC: 16404 AN: 40822

GnomAD4 genome AF: 0.371 AC: 56406 AN: 152032 Hom.: 10862 Cov.: 33 AF XY: 0.366 AC XY: 27226 AN XY: 74292

African (AFR) AF: 0.283 AC: 11756 AN: 41484

American (AMR) AF: 0.346 AC: 5283 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1438 AN: 3466

East Asian (EAS) AF: 0.453 AC: 2342 AN: 5166

South Asian (SAS) AF: 0.389 AC: 1872 AN: 4814

European-Finnish (FIN) AF: 0.343 AC: 3614 AN: 10538

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.426 AC: 28964 AN: 67956

Other (OTH) AF: 0.398 AC: 841 AN: 2114

Alfa AF: 0.409 Hom.: 1632

Bravo AF: 0.363

Asia WGS AF: 0.425 AC: 1477 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.1
DANN	Benign	0.63
PhyloP100		-0.031
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6917903; hg19: chr6-132147616; COSMIC: COSV62932086;