chr6-131877099-C-G

Variant names:

• chr6-131877099-C-G
• rs79079368
• NM_006208.3:c.1831C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006208.3(ENPP1):​c.1831C>G​(p.Leu611Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00417 in 1,614,056 control chromosomes in the GnomAD database, including 150 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (59 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (91 hom.)
• Consequence: ENPP1 NM_006208.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:7 O:1
• Conservation: PhyloP100: -0.177
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034568608).
• BP6: Variant 6-131877099-C-G is Benign according to our data. Variant chr6-131877099-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161093.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0148 (2252/152294) while in subpopulation AFR AF = 0.0481 (2000/41550). AF 95% confidence interval is 0.0464. There are 59 homozygotes in GnomAd4. There are 1104 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 59 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.1831C>G	p.Leu611Val	missense	Exon 18 of 25	NP_006199.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPP1	ENST00000647893.1	MANE Select	c.1831C>G	p.Leu611Val	missense	Exon 18 of 25	ENSP00000498074.1
	ENPP1	ENST00000459624.1	TSL:1	n.875C>G		non_coding_transcript_exon	Exon 10 of 10
	ENPP1	ENST00000922186.1		c.1699C>G	p.Leu567Val	missense	Exon 17 of 24	ENSP00000592245.1

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2246 AN: 152176 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.0481

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0321

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00958

GnomAD2 exomes AF: 0.00656 AC: 1648 AN: 251036 AF XY: 0.00674

Gnomad AFR exome AF: 0.0484

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00306 AC: 4479 AN: 1461762 Hom.: 91 Cov.: 31 AF XY: 0.00360 AC XY: 2618 AN XY: 727180

African (AFR) AF: 0.0506 AC: 1694 AN: 33478

American (AMR) AF: 0.00210 AC: 94 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39684

South Asian (SAS) AF: 0.0264 AC: 2280 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.000138 AC: 153 AN: 1111976

Other (OTH) AF: 0.00404 AC: 244 AN: 60390

GnomAD4 genome AF: 0.0148 AC: 2252 AN: 152294 Hom.: 59 Cov.: 32 AF XY: 0.0148 AC XY: 1104 AN XY: 74488

African (AFR) AF: 0.0481 AC: 2000 AN: 41550

American (AMR) AF: 0.00412 AC: 63 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0321 AC: 155 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68022

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.000782 Hom.: 0

Bravo AF: 0.0149

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0422 AC: 186

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00792 AC: 961

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Arterial calcification, generalized, of infancy, 1 (2)
1	-	-	Hypophosphatemic rickets (1)
-	-	1	Hypophosphatemic rickets, autosomal recessive, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.068
DANN	Benign	0.23
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.18
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.046
Sift	Benign	0.59	T
Sift4G	Benign	0.62	T
Polyphen		0.0010	B
Vest4		0.17
MVP		0.28
MPC		0.21
ClinPred		0.000027	T
GERP RS		-0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.41
Mutation Taster		=93/7	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: rs79079368; hg19: chr6-132198239;