8-119557583-G-A

Position:

• chr8-119557583-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001040092.3(ENPP2):​c.2530C>T​(p.Arg844Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00505 in 1,612,958 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (31 hom.)
• Consequence: ENPP2 NM_001040092.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.40

Genes affected

ENPP2 (HGNC:3357): (ectonucleotide pyrophosphatase/phosphodiesterase 2) The protein encoded by this gene functions as both a phosphodiesterase, which cleaves phosphodiester bonds at the 5' end of oligonucleotides, and a phospholipase, which catalyzes production of lysophosphatidic acid (LPA) in extracellular fluids. LPA evokes growth factor-like responses including stimulation of cell proliferation and chemotaxis. This gene product stimulates the motility of tumor cells and has angiogenic properties, and its expression is upregulated in several kinds of carcinomas. The gene product is secreted and further processed to make the biologically active form. Several alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008097917).
• BP6: Variant 8-119557583-G-A is Benign according to our data. Variant chr8-119557583-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 782143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-119557583-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP2	NM_001040092.3	c.2530C>T	p.Arg844Cys	missense_variant	25/25	ENST00000075322.11	NP_001035181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP2	ENST00000075322.11	c.2530C>T	p.Arg844Cys	missense_variant	25/25	1	NM_001040092.3	ENSP00000075322	P1

Frequencies

GnomAD3 genomes AF: 0.00418 AC: 636 AN: 152152 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00563

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00412 AC: 1030 AN: 250126 Hom.: 7 AF XY: 0.00412 AC XY: 558 AN XY: 135344

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00974

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.00492

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00514 AC: 7506 AN: 1460688 Hom.: 31 Cov.: 30 AF XY: 0.00507 AC XY: 3686 AN XY: 726692

Gnomad4 AFR exome AF: 0.000748

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00138

Gnomad4 FIN exome AF: 0.00807

Gnomad4 NFE exome AF: 0.00570

Gnomad4 OTH exome AF: 0.00408

GnomAD4 genome AF: 0.00418 AC: 636 AN: 152270 Hom.: 5 Cov.: 32 AF XY: 0.00445 AC XY: 331 AN XY: 74444

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0140

Gnomad4 NFE AF: 0.00563

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00490 Hom.: 2

Bravo AF: 0.00300

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00382 AC: 464

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 06, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	ENPP2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.0023	T
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.089	.;T;T;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
MetaRNN	Benign	0.0081	T;T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.7	.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.030	D;D;D;D;D
Polyphen		1.0	D;.;D;.;D
Vest4		0.39
MVP		0.84
MPC		0.94
ClinPred		0.015	T
GERP RS		6.0
Varity_R		0.53
gMVP		0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs61738778; hg19: chr8-120569823; COSMIC: COSV99030184;