chr5-36200275-G-A

Variant names:

• chr5-36200275-G-A
• rs587777772
• NM_001085411.3:c.1018C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001085411.3(NADK2):​c.1018C>T​(p.Arg340*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000254 in 1,576,690 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 Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NADK2 NM_001085411.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.253
• 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]

NADK2 Gene-Disease associations (from GenCC):

• progressive encephalopathy with leukodystrophy due to DECR deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-36200275-G-A is Pathogenic according to our data. Variant chr5-36200275-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 156239.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NADK2	NM_001085411.3	MANE Select	c.1018C>T	p.Arg340*	stop_gained	Exon 10 of 12	NP_001078880.1
	NADK2	NM_001287341.2		c.595C>T	p.Arg199*	stop_gained	Exon 11 of 13	NP_001274270.1
	NADK2	NM_001287340.2		c.529C>T	p.Arg177*	stop_gained	Exon 10 of 12	NP_001274269.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NADK2	ENST00000381937.9	TSL:2 MANE Select	c.1018C>T	p.Arg340*	stop_gained	Exon 10 of 12	ENSP00000371362.4
	NADK2	ENST00000282512.7	TSL:1	c.529C>T	p.Arg177*	stop_gained	Exon 10 of 12	ENSP00000282512.3
	NADK2	ENST00000617628.4	TSL:1	c.433C>T	p.Arg145*	stop_gained	Exon 6 of 8	ENSP00000480506.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151082 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1425608 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 709050

African (AFR) AF: 0.00 AC: 0 AN: 31702

American (AMR) AF: 0.0000243 AC: 1 AN: 41214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25068

East Asian (EAS) AF: 0.00 AC: 0 AN: 37892

South Asian (SAS) AF: 0.00 AC: 0 AN: 80616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1092676

Other (OTH) AF: 0.00 AC: 0 AN: 58456

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151082 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73708

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41142

American (AMR) AF: 0.00 AC: 0 AN: 15084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67802

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000187 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive encephalopathy with leukodystrophy due to DECR deficiency Pathogenic:2

Jun 20, 2019

Hadassah Hebrew University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 15, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.52	D
PhyloP100		0.25
Vest4		0.46
GERP RS		3.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587777772; hg19: chr5-36200377;