chr8-119580166-T-C

Position:

• chr8-119580166-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001040092.3(ENPP2):​c.1730A>G​(p.Asn577Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00125 in 1,612,356 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0013 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (41 hom.)
• Consequence: ENPP2 NM_001040092.3 missense, splice_region
• Scores: Splicing: ADA: 0.0003561
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.51

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035627186).
• BP6: Variant 8-119580166-T-C is Benign according to our data. Variant chr8-119580166-T-C is described in ClinVar as [Benign]. Clinvar id is 714512.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00127 (193/152372) while in subpopulation EAS AF= 0.0355 (184/5186). AF 95% confidence interval is 0.0313. There are 5 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• 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.1730A>G	p.Asn577Ser	missense_variant, splice_region_variant	19/25	ENST00000075322.11	NP_001035181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP2	ENST00000075322.11	c.1730A>G	p.Asn577Ser	missense_variant, splice_region_variant	19/25	1	NM_001040092.3	ENSP00000075322	P1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152254 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0354

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00314 AC: 789 AN: 251370 Hom.: 18 AF XY: 0.00283 AC XY: 385 AN XY: 135856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0418

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00124 AC: 1816 AN: 1459984 Hom.: 41 Cov.: 28 AF XY: 0.00119 AC XY: 861 AN XY: 726470

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0422

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152372 Hom.: 5 Cov.: 32 AF XY: 0.00127 AC XY: 95 AN XY: 74516

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0355

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00154 Hom.: 3

Bravo AF: 0.00177

ExAC AF: 0.00309 AC: 375

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.014	.;T;T;.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T;D;T;D;T
MetaRNN	Benign	0.0036	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;.;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.89	N;N;N;N;N
REVEL	Benign	0.082
Sift	Benign	0.57	T;T;T;T;T
Sift4G	Benign	0.73	T;T;T;T;T
Polyphen		0.0050	B;.;B;.;B
Vest4		0.12
MVP		0.77
MPC		0.17
ClinPred		0.014	T
GERP RS		3.5
Varity_R		0.056
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00036
dbscSNV1_RF	Benign	0.088
SpliceAI score (max)		0.12		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: rs2289886; hg19: chr8-120592406; COSMIC: COSV50015536; COSMIC: COSV50015536;