6-131889981-G-C

Variant names:

• chr6-131889981-G-C
• rs1974201
• NM_006208.3:c.2608-360G>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.2608-360G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 149,942 control chromosomes in the GnomAD database, including 8,488 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 0.31 (8488 hom., cov: 32)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 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.2608-360G>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.2608-360G>C		intron	N/A	ENSP00000498074.1	P22413
	ENPP1	ENST00000922186.1		c.2476-360G>C		intron	N/A	ENSP00000592245.1
	ENPP1	ENST00000513998.5	TSL:5	n.*1445-360G>C		intron	N/A	ENSP00000422424.1	E9PE72

Frequencies

GnomAD3 genomes AF: 0.311 AC: 46644 AN: 149822 Hom.: 8482 Cov.: 32

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.391

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.436

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.321

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

GnomAD4 genome AF: 0.311 AC: 46696 AN: 149942 Hom.: 8488 Cov.: 32 AF XY: 0.315 AC XY: 23056 AN XY: 73194

African (AFR) AF: 0.440 AC: 18188 AN: 41304

American (AMR) AF: 0.405 AC: 6156 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 1338 AN: 3420

East Asian (EAS) AF: 0.582 AC: 3000 AN: 5156

South Asian (SAS) AF: 0.395 AC: 1871 AN: 4742

European-Finnish (FIN) AF: 0.163 AC: 1644 AN: 10102

Middle Eastern (MID) AF: 0.432 AC: 126 AN: 292

European-Non Finnish (NFE) AF: 0.202 AC: 13454 AN: 66752

Other (OTH) AF: 0.323 AC: 677 AN: 2096

Alfa AF: 0.105 Hom.: 142

Bravo AF: 0.333

Asia WGS AF: 0.510 AC: 1769 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.3
DANN	Benign	0.29
PhyloP100		0.36
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: rs1974201; hg19: chr6-132211121;