5-36197535-G-A
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001085411.3(NADK2):c.1190+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,612,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
NADK2
NM_001085411.3 splice_donor_region, intron
NM_001085411.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0006424
2
Clinical Significance
Conservation
PhyloP100: 2.05
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.59).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NADK2 | NM_001085411.3 | c.1190+6C>T | splice_donor_region_variant, intron_variant | ENST00000381937.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NADK2 | ENST00000381937.9 | c.1190+6C>T | splice_donor_region_variant, intron_variant | 2 | NM_001085411.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152056Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250182Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135242
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GnomAD4 exome AF: 0.0000226 AC: 33AN: 1460014Hom.: 0 Cov.: 31 AF XY: 0.0000262 AC XY: 19AN XY: 726300
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 152056Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74270
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 21, 2022 | The c.1190+6C>T intronic alteration consists of a C to T substitution nucleotides after coding exon 11 in the NADK2 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Progressive encephalopathy with leukodystrophy due to DECR deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 29, 2020 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with NADK2-related conditions. This variant is present in population databases (rs377615419, ExAC 0.003%). This sequence change falls in intron 11 of the NADK2 gene. It does not directly change the encoded amino acid sequence of the NADK2 protein. It affects a nucleotide within the consensus splice site of the intron. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at