Genetic Variant ETNK2:p.Val109Met (chr1-204149896-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018208.4(ETNK2):c.325G>A(p.Val109Met) variant causes a missense change. The variant allele was found at a frequency of 0.000019 in 1,579,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

ETNK2
NM_018208.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.51

Variant links:

Genes affected

ETNK2 (HGNC:25575): (ethanolamine kinase 2) The protein encoded by this gene is a member of choline/ethanolamine kinase family which catalyzes the first step of phosphatidylethanolamine (PtdEtn) biosynthesis via the cytidine diphosphate (CDP) ethanolamine pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ETNK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETNK2	NM_018208.4 link	c.325G>A	p.Val109Met	missense_variant	Exon 2 of 8	ENST00000367202.9	NP_060678.2	Q9NVF9-1A0A024R9A8
ETNK2	NM_001297760.2 link	c.325G>A	p.Val109Met	missense_variant	Exon 2 of 8		NP_001284689.1	Q9NVF9-2A0A024R976
ETNK2	NM_001297762.2 link	c.325G>A	p.Val109Met	missense_variant	Exon 2 of 7		NP_001284691.1	Q9NVF9-3
ETNK2	NM_001297761.2 link	c.-17+1699G>A		intron_variant	Intron 1 of 6		NP_001284690.1	Q9NVF9B7Z1G7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ETNK2	ENST00000367202.9 link	c.325G>A	p.Val109Met	missense_variant	Exon 2 of 8	1	NM_018208.4	ENSP00000356170.4	Q9NVF9-1
ETNK2	ENST00000367201.7 link	c.325G>A	p.Val109Met	missense_variant	Exon 2 of 8	2		ENSP00000356169.3	Q9NVF9-2
ETNK2	ENST00000429525.1 link	c.13G>A	p.Val5Met	missense_variant	Exon 3 of 3	4		ENSP00000394618.1	B7ZC35
ETNK2	ENST00000444817.1 link	c.-15G>A		upstream_gene_variant		5		ENSP00000406241.1	Q5SXX7

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151840

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000309

AC:

AN:

194356

Hom.:

AF XY:

0.0000192

AC XY:

AN XY:

104012

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000106

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000402

Gnomad FIN exome

AF:

0.0000554

Gnomad NFE exome

AF:

0.0000120

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000203

AC:

AN:

1427206

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

706670

show subpopulations

Gnomad4 AFR exome

AF:

0.0000307

Gnomad4 AMR exome

AF:

0.0000757

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000267

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.0000392

Gnomad4 NFE exome

AF:

0.0000174

Gnomad4 OTH exome

AF:

0.0000338

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151840

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74142

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.325G>A (p.V109M) alteration is located in exon 2 (coding exon 2) of the ETNK2 gene. This alteration results from a G to A substitution at nucleotide position 325, causing the valine (V) at amino acid position 109 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

.;T;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.89

D;D;.

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Uncertain

0.10

MutationAssessor

Pathogenic

3.0

M;M;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.4

N;N;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.021

D;D;.

Sift4G

Uncertain

0.0020

D;D;.

Polyphen

0.62

P;D;.

Vest4

0.40

MutPred

0.74

Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);.;

MVP

0.57

MPC

0.52

ClinPred

0.72

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over