NM_001085411.3:c.1191-64T>C

Variant names:

• chr5-36195346-A-G
• rs11952882
• NM_001085411.3:c.1191-64T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001085411.3(NADK2):​c.1191-64T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,465,232 control chromosomes in the GnomAD database, including 212,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (16068 hom., cov: 32)
  • Exomes 𝑓: 0.53 (196240 hom.)
• Consequence: NADK2 NM_001085411.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.625
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 5-36195346-A-G is Benign according to our data. Variant chr5-36195346-A-G is described in ClinVar as Benign. ClinVar VariationId is 1235193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

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.1191-64T>C		intron	N/A	NP_001078880.1	Q4G0N4-1
	NADK2	NM_001287341.2		c.768-64T>C		intron	N/A	NP_001274270.1	B7Z8V7
	NADK2	NM_001287340.2		c.702-64T>C		intron	N/A	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.1191-64T>C		intron	N/A	ENSP00000371362.4	Q4G0N4-1
	NADK2	ENST00000282512.7	TSL:1	c.702-64T>C		intron	N/A	ENSP00000282512.3	Q4G0N4-3
	NADK2	ENST00000617628.4	TSL:1	c.606-64T>C		intron	N/A	ENSP00000480506.1	A0A0C4DGV3

Frequencies

GnomAD3 genomes AF: 0.419 AC: 63607 AN: 151926 Hom.: 16069 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.586

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.0857

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.430

GnomAD4 exome AF: 0.533 AC: 699310 AN: 1313188 Hom.: 196240 AF XY: 0.528 AC XY: 341588 AN XY: 646614

African (AFR) AF: 0.160 AC: 4306 AN: 26850

American (AMR) AF: 0.361 AC: 9263 AN: 25664

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 12097 AN: 20878

East Asian (EAS) AF: 0.0885 AC: 3011 AN: 34026

South Asian (SAS) AF: 0.260 AC: 16837 AN: 64786

European-Finnish (FIN) AF: 0.542 AC: 26612 AN: 49076

Middle Eastern (MID) AF: 0.426 AC: 2255 AN: 5296

European-Non Finnish (NFE) AF: 0.580 AC: 598668 AN: 1032436

Other (OTH) AF: 0.485 AC: 26261 AN: 54176

GnomAD4 genome AF: 0.418 AC: 63605 AN: 152044 Hom.: 16068 Cov.: 32 AF XY: 0.411 AC XY: 30544 AN XY: 74318

African (AFR) AF: 0.169 AC: 7033 AN: 41496

American (AMR) AF: 0.427 AC: 6531 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1966 AN: 3470

East Asian (EAS) AF: 0.0861 AC: 445 AN: 5168

South Asian (SAS) AF: 0.247 AC: 1190 AN: 4822

European-Finnish (FIN) AF: 0.542 AC: 5725 AN: 10566

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.576 AC: 39140 AN: 67930

Other (OTH) AF: 0.426 AC: 899 AN: 2108

Alfa AF: 0.366 Hom.: 1135

Bravo AF: 0.400

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.40
DANN	Benign	0.24
PhyloP100		-0.63
Mutation Taster		=100/0	polymorphism (auto)

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: rs11952882; hg19: chr5-36195448; COSMIC: COSV56936241;