dbSNP rs1277388010: NADK2:p.Met1? (chr5-36241798-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_001085411.3(NADK2):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000833 in 1,320,180 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: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

NADK2
NM_001085411.3 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 0.789

Publications

4 publications found

Variant links:

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: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics

NADK2 links:

LOC124900962 (HGNC:):

LOC124900962 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 164 codons. Genomic position: 36225612. Lost 0.369 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NADK2	NM_001085411.3	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	NP_001078880.1	Q4G0N4-1
NADK2	NM_001287341.2		c.-190+298A>G		intron	N/A	NP_001274270.1	B7Z8V7
NADK2	NM_153013.5		c.-190+298A>G		intron	N/A	NP_694558.1	Q4G0N4-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NADK2	ENST00000381937.9	TSL:2 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	ENSP00000371362.4	Q4G0N4-1
NADK2	ENST00000282512.7	TSL:1	c.-190+298A>G		intron	N/A	ENSP00000282512.3	Q4G0N4-3
NADK2	ENST00000948923.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 13	ENSP00000618982.1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151468

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000263

AC:

AN:

38090

AF XY:

0.0000434

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000668

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1168712

Hom.:

Cov.:

AF XY:

0.00000698

AC XY:

AN XY:

572662

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22870

American (AMR)

AF:

0.00

AC:

AN:

13890

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17694

East Asian (EAS)

AF:

0.00

AC:

AN:

24068

South Asian (SAS)

AF:

0.00

AC:

AN:

50622

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3134

European-Non Finnish (NFE)

AF:

0.00000829

AC:

AN:

965582

Other (OTH)

AF:

0.00

AC:

AN:

45780

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151468

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73962

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41308

American (AMR)

AF:

0.00

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67826

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Progressive encephalopathy with leukodystrophy due to DECR deficiency (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0022

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.96

MetaSVM

Benign

-0.88

PhyloP100

0.79

PROVEAN

Benign

-0.80

REVEL

Benign

0.21

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.035

Vest4

0.60

MutPred

0.82

Gain of sheet (P = 0.0477)

MVP

0.16

ClinPred

0.42

GERP RS

4.3

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.96

gMVP

0.59

Mutation Taster

=32/68

disease causing

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over