1-204149961-C-T

Variant names:

• chr1-204149961-C-T
• rs374386002
• NM_018208.4:c.260G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018208.4(ETNK2):​c.260G>A​(p.Arg87His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000491 in 1,222,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: ETNK2 NM_018208.4 missense, splice_region
• Scores: Splicing: ADA: 0.01952
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07579872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETNK2	NM_018208.4	c.260G>A	p.Arg87His	missense_variant, splice_region_variant	Exon 2 of 8	ENST00000367202.9	NP_060678.2
ETNK2	NM_001297760.2	c.260G>A	p.Arg87His	missense_variant, splice_region_variant	Exon 2 of 8		NP_001284689.1
ETNK2	NM_001297762.2	c.260G>A	p.Arg87His	missense_variant, splice_region_variant	Exon 2 of 7		NP_001284691.1
ETNK2	NM_001297761.2	c.-17+1634G>A		intron_variant	Intron 1 of 6		NP_001284690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETNK2	ENST00000367202.9	c.260G>A	p.Arg87His	missense_variant, splice_region_variant	Exon 2 of 8	1	NM_018208.4	ENSP00000356170.4

Frequencies

GnomAD3 genomes AF: 0.0000670 AC: 9 AN: 134342 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000815

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00357

Gnomad NFE AF: 0.0000631

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000328 AC: 5 AN: 152476 Hom.: 0 AF XY: 0.0000373 AC XY: 3 AN XY: 80408

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000442

Gnomad FIN exome AF: 0.0000683

Gnomad NFE exome AF: 0.0000518

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000469 AC: 51 AN: 1088112 Hom.: 0 Cov.: 38 AF XY: 0.0000485 AC XY: 26 AN XY: 535820

Gnomad4 AFR exome AF: 0.000259

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000792

Gnomad4 SAS exome AF: 0.0000532

Gnomad4 FIN exome AF: 0.000218

Gnomad4 NFE exome AF: 0.0000371

Gnomad4 OTH exome AF: 0.0000506

GnomAD4 genome AF: 0.0000670 AC: 9 AN: 134428 Hom.: 0 Cov.: 31 AF XY: 0.0000776 AC XY: 5 AN XY: 64392

Gnomad4 AFR AF: 0.0000813

Gnomad4 AMR AF: 0.0000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000631

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000575 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000944 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.260G>A (p.R87H) 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 260, causing the arginine (R) at amino acid position 87 to be replaced by a histidine (H). 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	Benign	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.049	.;T
Eigen	Benign	0.010
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.076	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.15
Sift	Benign	0.41	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.098	B;B
Vest4		0.23
MVP		0.51
MPC		0.35
ClinPred		0.16	T
GERP RS		4.6
Varity_R		0.071
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.020
dbscSNV1_RF	Benign	0.16
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: rs374386002; hg19: chr1-204119089;