NM_006208.3:c.27C>G

Variant names:

• chr6-131808062-C-G
• rs794726927
• NM_006208.3:c.27C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_006208.3(ENPP1):​c.27C>G​(p.Gly9Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENPP1 NM_006208.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.487
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 6-131808062-C-G is Benign according to our data. Variant chr6-131808062-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193333.
• BP7: Synonymous conserved (PhyloP=-0.487 with no splicing effect.

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.27C>G	p.Gly9Gly	synonymous	Exon 1 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.27C>G	p.Gly9Gly	synonymous	Exon 1 of 25	ENSP00000498074.1	P22413
	ENPP1	ENST00000922186.1		c.27C>G	p.Gly9Gly	synonymous	Exon 1 of 24	ENSP00000592245.1
	ENPP1	ENST00000486853.1	TSL:2	n.47C>G		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.000391 AC: 15 AN: 38368 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000475

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000998

Gnomad ASJ AF: 0.000984

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000824

Gnomad FIN AF: 0.000633

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000218

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 558104 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 260634

African (AFR) AF: 0.00 AC: 0 AN: 10912

American (AMR) AF: 0.00 AC: 0 AN: 1210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3704

East Asian (EAS) AF: 0.00 AC: 0 AN: 3032

South Asian (SAS) AF: 0.00 AC: 0 AN: 10968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1118

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 506662

Other (OTH) AF: 0.00 AC: 0 AN: 18634

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000365 AC: 14 AN: 38380 Hom.: 0 Cov.: 0 AF XY: 0.000369 AC XY: 7 AN XY: 18984

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000474 AC: 5 AN: 10556

American (AMR) AF: 0.000664 AC: 2 AN: 3010

Ashkenazi Jewish (ASJ) AF: 0.000984 AC: 1 AN: 1016

East Asian (EAS) AF: 0.00 AC: 0 AN: 1702

South Asian (SAS) AF: 0.000826 AC: 1 AN: 1210

European-Finnish (FIN) AF: 0.000633 AC: 1 AN: 1580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 110

European-Non Finnish (NFE) AF: 0.000218 AC: 4 AN: 18374

Other (OTH) AF: 0.00 AC: 0 AN: 538

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.53
PhyloP100		-0.49
PromoterAI		0.076	Neutral
Mutation Taster		=100/0	polymorphism

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: rs794726927; hg19: chr6-132129202; COSMIC: COSV62934231;