5-36195248-T-C

Position:

• chr5-36195248-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001085411.3(NADK2):​c.1225A>G​(p.Met409Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000651 in 1,612,168 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (2 hom.)
• Consequence: NADK2 NM_001085411.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2 O:1
• Conservation: PhyloP100: 7.54

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0910247).
• BP6: Variant 5-36195248-T-C is Benign according to our data. Variant chr5-36195248-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 798229.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NADK2	NM_001085411.3	c.1225A>G	p.Met409Val	missense_variant	12/12	ENST00000381937.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NADK2	ENST00000381937.9	c.1225A>G	p.Met409Val	missense_variant	12/12	2	NM_001085411.3	P1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000462 AC: 115 AN: 249136 Hom.: 0 AF XY: 0.000460 AC XY: 62 AN XY: 134664

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000417

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000574

Gnomad OTH exome AF: 0.000995

GnomAD4 exome AF: 0.000658 AC: 961 AN: 1459988 Hom.: 2 Cov.: 30 AF XY: 0.000687 AC XY: 499 AN XY: 726216

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000473

Gnomad4 ASJ exome AF: 0.00353

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000717

Gnomad4 OTH exome AF: 0.000763

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000525 AC XY: 39 AN XY: 74344

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000919 Hom.: 0

Bravo AF: 0.000499

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000371 AC: 45

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Progressive encephalopathy with leukodystrophy due to DECR deficiency Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Uncertain significance and reported on 10-14-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 30, 2021

The c.1225A>G (p.M409V) alteration is located in exon 12 (coding exon 12) of the NADK2 gene. This alteration results from a A to G substitution at nucleotide position 1225, causing the methionine (M) at amino acid position 409 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

NADK2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	.;.;T;.;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.091	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.5	N;N;N;N;.;N
REVEL	Uncertain	0.60
Sift	Benign	0.085	T;T;T;T;.;T
Sift4G	Uncertain	0.058	T;T;T;T;T;T
Polyphen		0.96, 0.92, 0.040	.;.;D;P;.;B
Vest4		0.75
MVP		0.58
MPC		0.52
ClinPred		0.055	T
GERP RS		5.9
Varity_R		0.27
gMVP		0.84

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: rs62353845; hg19: chr5-36195350;