6-131829299-A-G

Variant names:

• chr6-131829299-A-G
• rs2021966
• NM_006208.3:c.241-18477A>G

Variant summary

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

The NM_006208.3(ENPP1):​c.241-18477A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 152,142 control chromosomes in the GnomAD database, including 14,480 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 0.43 (14480 hom., cov: 33)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.134
• Publications: 16 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
• hypopigmentation-punctate palmoplantar keratoderma syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.241-18477A>G		intron_variant	Intron 1 of 24	ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.241-18477A>G		intron_variant	Intron 1 of 24		NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000486853.1	n.261-18477A>G		intron_variant	Intron 1 of 3	2
ENPP1	ENST00000513998.5	n.241-18477A>G		intron_variant	Intron 1 of 24	5		ENSP00000422424.1
ENPP1	ENST00000650507.1	n.*76+3184A>G		intron_variant	Intron 2 of 3			ENSP00000497375.1

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64770 AN: 152024 Hom.: 14480 Cov.: 33

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.448

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.426 AC: 64789 AN: 152142 Hom.: 14480 Cov.: 33 AF XY: 0.426 AC XY: 31642 AN XY: 74362

African (AFR) AF: 0.312 AC: 12939 AN: 41496

American (AMR) AF: 0.467 AC: 7142 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1463 AN: 3470

East Asian (EAS) AF: 0.699 AC: 3619 AN: 5176

South Asian (SAS) AF: 0.447 AC: 2158 AN: 4826

European-Finnish (FIN) AF: 0.390 AC: 4117 AN: 10562

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.471 AC: 32057 AN: 67998

Other (OTH) AF: 0.448 AC: 948 AN: 2114

Alfa AF: 0.458 Hom.: 31250

Bravo AF: 0.425

Asia WGS AF: 0.546 AC: 1898 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.1
DANN	Benign	0.75
PhyloP100		-0.13
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: rs2021966; hg19: chr6-132150439;