6-46161424-C-G

Variant names:

• chr6-46161424-C-G
• rs939264788
• NM_001290072.2:c.1336G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001290072.2(ENPP5):​c.1336G>C​(p.Val446Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ENPP5 NM_001290072.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.52
• Publications: 0 publications found

Genes affected

ENPP5 (HGNC:13717): (ectonucleotide pyrophosphatase/phosphodiesterase family member 5) This gene encodes a type-I transmembrane glycoprotein. Studies in rat suggest the encoded protein may play a role in neuronal cell communications. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11580515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP5	NM_001290072.2	c.1336G>C	p.Val446Leu	missense_variant	Exon 5 of 5	ENST00000371383.7	NP_001277001.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP5	ENST00000371383.7	c.1336G>C	p.Val446Leu	missense_variant	Exon 5 of 5	1	NM_001290072.2	ENSP00000360436.1
ENPP5	ENST00000230565.3	c.1336G>C	p.Val446Leu	missense_variant	Exon 4 of 4	1		ENSP00000230565.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461420 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727028

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111666

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0043	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.066
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	.;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		2.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.067
Sift	Benign	0.12	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.033	B;B
Vest4		0.26
MutPred		0.43		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.45
MPC		0.20
ClinPred		0.22	T
GERP RS		3.1
Varity_R		0.081
gMVP		0.46
Mutation Taster		=98/2	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: rs939264788; hg19: chr6-46129161;