5-36195346-A-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001085411.3(NADK2):​c.1191-64T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000817 in 1,467,314 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0044 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (4 hom.)
• Consequence: NADK2 NM_001085411.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-36195346-A-C is Benign according to our data. Variant chr5-36195346-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1321582.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000402 (529/1315196) while in subpopulation AFR AF = 0.0166 (445/26870). AF 95% confidence interval is 0.0153. There are 4 homozygotes in GnomAdExome4. There are 233 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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

Frequencies

GnomAD3 genomes AF: 0.00439 AC: 667 AN: 152000 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.0000588

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.000402 AC: 529 AN: 1315196 Hom.: 4 AF XY: 0.000360 AC XY: 233 AN XY: 647594

African (AFR) AF: 0.0166 AC: 445 AN: 26870

American (AMR) AF: 0.000933 AC: 24 AN: 25718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20914

East Asian (EAS) AF: 0.00 AC: 0 AN: 34044

South Asian (SAS) AF: 0.0000154 AC: 1 AN: 64918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49128

Middle Eastern (MID) AF: 0.000755 AC: 4 AN: 5298

European-Non Finnish (NFE) AF: 0.00000484 AC: 5 AN: 1034038

Other (OTH) AF: 0.000921 AC: 50 AN: 54268

GnomAD4 genome AF: 0.00440 AC: 670 AN: 152118 Hom.: 7 Cov.: 32 AF XY: 0.00413 AC XY: 307 AN XY: 74362

African (AFR) AF: 0.0152 AC: 632 AN: 41514

American (AMR) AF: 0.00157 AC: 24 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67964

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00 Hom.: 1135

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.37
DANN	Benign	0.29
PhyloP100		-0.63
Mutation Taster		=100/0	polymorphism

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;