chr5-36195263-A-C

Position:

• chr5-36195263-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001085411.3(NADK2):​c.1210T>G​(p.Cys404Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NADK2 NM_001085411.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NADK2	NM_001085411.3	c.1210T>G	p.Cys404Gly	missense_variant	12/12	ENST00000381937.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NADK2	ENST00000381937.9	c.1210T>G	p.Cys404Gly	missense_variant	12/12	2	NM_001085411.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 247070 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133546

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000303

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458610 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725502

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000454

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive encephalopathy with leukodystrophy due to DECR deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 404 of the NADK2 protein (p.Cys404Gly). 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. 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. This variant is present in population databases (rs775092555, gnomAD 0.003%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Benign	0.97
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.5	D;D;D;D;.;D
REVEL	Uncertain	0.51
Sift	Benign	0.20	T;T;T;T;.;T
Sift4G	Benign	0.24	T;T;T;T;T;T
Polyphen		0.96, 1.0, 0.14	.;.;P;D;.;B
Vest4		0.85
MutPred		0.69		.;.;Gain of sheet (P = 0.0016);.;.;.;
MVP		0.60
MPC		1.4
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.76
gMVP		0.97

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

Other links and lift over

dbSNP: rs775092555; hg19: chr5-36195365;