Variant rs779870872 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001085411.3(NADK2):c.388C>T(p.Arg130Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000609 in 1,495,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

NADK2
NM_001085411.3 missense, splice_region

Scores

Splicing: ADA: 0.5539

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60

Variant links:

Genes affected

NADK2 (HGNC:26404): (NAD kinase 2, mitochondrial) This gene encodes a mitochondrial kinase that catalyzes the phosphorylation of NAD to yield NADP. Mutations in this gene result in 2,4-dienoyl-CoA reductase deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

NADK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35662764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NADK2	NM_001085411.3 linkuse as main transcript	c.388C>T	p.Arg130Trp	missense_variant, splice_region_variant	2/12	ENST00000381937.9	NP_001078880.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NADK2	ENST00000381937.9 linkuse as main transcript	c.388C>T	p.Arg130Trp	missense_variant, splice_region_variant	2/12	2	NM_001085411.3	ENSP00000371362	P1	Q4G0N4-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000640

AC:

AN:

1343198

Hom.:

Cov.:

AF XY:

0.0000724

AC XY:

AN XY:

662548

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000772

Gnomad4 OTH exome

AF:

0.0000719

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000832

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000257

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Progressive encephalopathy with leukodystrophy due to DECR deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 21, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 578808). This variant has not been reported in the literature in individuals affected with NADK2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 130 of the NADK2 protein (p.Arg130Trp). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

T;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.36

T;T

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.2

M;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-4.3

D;D

REVEL

Benign

0.28

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.39

MutPred

0.43

Loss of disorder (P = 0.0662);Loss of disorder (P = 0.0662);

MVP

0.68

MPC

1.3

ClinPred

0.74

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.55

dbscSNV1_RF

Benign

0.51

SpliceAI score (max)

0.010

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