chr5-36195263-A-C

Variant names:

• chr5-36195263-A-C
• rs775092555
• NM_001085411.3:c.1210T>G

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001085411.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NADK2	NM_001085411.3	MANE Select	c.1210T>G	p.Cys404Gly	missense	Exon 12 of 12	NP_001078880.1	Q4G0N4-1
	NADK2	NM_001287341.2		c.787T>G	p.Cys263Gly	missense	Exon 13 of 13	NP_001274270.1	B7Z8V7
	NADK2	NM_001287340.2		c.721T>G	p.Cys241Gly	missense	Exon 12 of 12	NP_001274269.1	Q4G0N4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NADK2	ENST00000381937.9	TSL:2 MANE Select	c.1210T>G	p.Cys404Gly	missense	Exon 12 of 12	ENSP00000371362.4	Q4G0N4-1
	NADK2	ENST00000282512.7	TSL:1	c.721T>G	p.Cys241Gly	missense	Exon 12 of 12	ENSP00000282512.3	Q4G0N4-3
	NADK2	ENST00000617628.4	TSL:1	c.625T>G	p.Cys209Gly	missense	Exon 8 of 8	ENSP00000480506.1	A0A0C4DGV3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 247070 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33274

American (AMR) AF: 0.0000454 AC: 2 AN: 44094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.00 AC: 0 AN: 85390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110858

Other (OTH) AF: 0.00 AC: 0 AN: 60256

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Progressive encephalopathy with leukodystrophy due to DECR deficiency (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.078	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.7	L
PhyloP100		8.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.5	D
REVEL	Uncertain	0.51
Sift	Benign	0.20	T
Sift4G	Benign	0.24	T
Polyphen		0.96	P
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
Mutation Taster		=18/82	disease causing

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

Other links and lift over

dbSNP: rs775092555; hg19: chr5-36195365;