5-36195203-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001085411.3(NADK2):ā€‹c.1270A>Gā€‹(p.Ile424Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000905 in 1,613,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000059 ( 0 hom., cov: 32)
Exomes š‘“: 0.000094 ( 0 hom. )

Consequence

NADK2
NM_001085411.3 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.74
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]
SKP2 (HGNC:10901): (S-phase kinase associated protein 2) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class; in addition to an F-box, this protein contains 10 tandem leucine-rich repeats. This protein is an essential element of the cyclin A-CDK2 S-phase kinase. It specifically recognizes phosphorylated cyclin-dependent kinase inhibitor 1B (CDKN1B, also referred to as p27 or KIP1) predominantly in S phase and interacts with S-phase kinase-associated protein 1 (SKP1 or p19). In addition, this gene is established as a protooncogene causally involved in the pathogenesis of lymphomas. Alternative splicing of this gene generates three transcript variants encoding different isoforms. [provided by RefSeq, Jul 2011]

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ACMG classification

Classification made for transcript

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=0.14557472).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NADK2NM_001085411.3 linkuse as main transcriptc.1270A>G p.Ile424Val missense_variant 12/12 ENST00000381937.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NADK2ENST00000381937.9 linkuse as main transcriptc.1270A>G p.Ile424Val missense_variant 12/122 NM_001085411.3 P1Q4G0N4-1

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152156
Hom.:
0
Cov.:
32
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:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000958
AC:
24
AN:
250642
Hom.:
0
AF XY:
0.0000886
AC XY:
12
AN XY:
135466
show subpopulations
Gnomad AFR exome
AF:
0.0000617
Gnomad AMR exome
AF:
0.0000292
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000984
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000167
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000937
AC:
137
AN:
1461376
Hom.:
0
Cov.:
30
AF XY:
0.0000963
AC XY:
70
AN XY:
726962
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000448
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000103
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152274
Hom.:
0
Cov.:
32
AF XY:
0.000107
AC XY:
8
AN XY:
74454
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:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000604
Hom.:
0
Bravo
AF:
0.0000642
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000132
AC:
16
EpiCase
AF:
0.000164
EpiControl
AF:
0.000357

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 11, 2024This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 424 of the NADK2 protein (p.Ile424Val). This variant is present in population databases (rs138382380, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NADK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 959061). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NADK2 protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0022
.;.;T;.;.;.
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.91
.;D;D;D;D;D
M_CAP
Benign
0.0027
T
MetaRNN
Benign
0.15
T;T;T;T;T;T
MetaSVM
Benign
-0.71
T
MutationAssessor
Benign
1.4
.;.;L;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-0.020
N;N;N;N;.;N
REVEL
Benign
0.23
Sift
Benign
0.92
T;T;T;T;.;T
Sift4G
Benign
0.49
T;T;T;T;T;T
Polyphen
0.91, 0.99, 0.84
.;.;P;D;.;P
Vest4
0.27
MVP
0.27
MPC
0.89
ClinPred
0.14
T
GERP RS
5.9
Varity_R
0.077
gMVP
0.45

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.

Other links and lift over

dbSNP: rs138382380; hg19: chr5-36195305; COSMIC: COSV56939175; API