1-183286725-G-C
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2
The NM_015039.4(NMNAT2):c.385C>G(p.Pro129Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,612,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
NMNAT2
NM_015039.4 missense
NM_015039.4 missense
Scores
1
7
11
Clinical Significance
Conservation
PhyloP100: 6.54
Publications
0 publications found
Genes affected
NMNAT2 (HGNC:16789): (nicotinamide nucleotide adenylyltransferase 2) This gene product belongs to the nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme family, members of which catalyze an essential step in NAD (NADP) biosynthetic pathway. Unlike the other human family member, which is localized to the nucleus, and is ubiquitously expressed; this enzyme is cytoplasmic, and is predominantly expressed in the brain. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.1005 (below the threshold of 3.09). Trascript score misZ: 2.0325 (below the threshold of 3.09).
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NMNAT2 | ENST00000287713.7 | c.385C>G | p.Pro129Ala | missense_variant | Exon 5 of 11 | 1 | NM_015039.4 | ENSP00000287713.6 | ||
| NMNAT2 | ENST00000294868.8 | c.370C>G | p.Pro124Ala | missense_variant | Exon 5 of 11 | 1 | ENSP00000294868.4 | |||
| NMNAT2 | ENST00000473046.1 | n.255C>G | non_coding_transcript_exon_variant | Exon 3 of 5 | 1 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152176Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
2
AN:
152176
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460066Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726264 show subpopulations
GnomAD4 exome
AF:
AC:
2
AN:
1460066
Hom.:
Cov.:
30
AF XY:
AC XY:
1
AN XY:
726264
show subpopulations
African (AFR)
AF:
AC:
2
AN:
33464
American (AMR)
AF:
AC:
0
AN:
44374
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26128
East Asian (EAS)
AF:
AC:
0
AN:
39666
South Asian (SAS)
AF:
AC:
0
AN:
85630
European-Finnish (FIN)
AF:
AC:
0
AN:
53408
Middle Eastern (MID)
AF:
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111292
Other (OTH)
AF:
AC:
0
AN:
60338
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.0000131 AC: 2AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74328 show subpopulations
GnomAD4 genome
AF:
AC:
2
AN:
152176
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74328
show subpopulations
African (AFR)
AF:
AC:
2
AN:
41442
American (AMR)
AF:
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5188
South Asian (SAS)
AF:
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68032
Other (OTH)
AF:
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Apr 20, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.385C>G (p.P129A) alteration is located in exon 5 (coding exon 5) of the NMNAT2 gene. This alteration results from a C to G substitution at nucleotide position 385, causing the proline (P) at amino acid position 129 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
DANN
Benign
DEOGEN2
Benign
.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;N
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;D
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MutPred
0.41
.;Loss of disorder (P = 0.0534);
MVP
MPC
0.90
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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