5-36197556-C-T

Variant summary

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

The NM_001085411.3(NADK2):​c.1175G>A​(p.Arg392His) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,612,122 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 (★). Synonymous variant affecting the same amino acid position (i.e. R392R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

NADK2
NM_001085411.3 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.10
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]

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=0.3612221).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NADK2NM_001085411.3 linkuse as main transcriptc.1175G>A p.Arg392His missense_variant 11/12 ENST00000381937.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NADK2ENST00000381937.9 linkuse as main transcriptc.1175G>A p.Arg392His missense_variant 11/122 NM_001085411.3 P1Q4G0N4-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151990
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250168
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135242
show subpopulations
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000266
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000685
AC:
10
AN:
1460132
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726344
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:
0.00000810
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151990
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74220
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:
0.0000332
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000247
AC:
3

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), LabcorpApr 09, 2023In 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. 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. 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 histidine, which is basic and polar, at codon 392 of the NADK2 protein (p.Arg392His). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.34
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.11
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.16
.;.;T;.;.;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
.;D;D;D;D;D
M_CAP
Benign
0.0090
T
MetaRNN
Benign
0.36
T;T;T;T;T;T
MetaSVM
Benign
-0.45
T
MutationAssessor
Pathogenic
3.0
.;.;M;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-3.6
D;D;D;D;.;D
REVEL
Uncertain
0.32
Sift
Pathogenic
0.0
D;D;D;D;.;D
Sift4G
Uncertain
0.048
D;D;D;D;D;D
Polyphen
1.0
.;.;D;D;.;D
Vest4
0.55
MVP
0.32
MPC
0.65
ClinPred
0.98
D
GERP RS
5.3
Varity_R
0.68
gMVP
0.86

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: rs772840407; hg19: chr5-36197658; COSMIC: COSV99237286; API