1-183261260-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate

The NM_015039.4(NMNAT2):c.695G>A(p.Arg232Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,708 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

NMNAT2
NM_015039.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.60

Publications

9 publications found

Variant links:

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]

NMNAT2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity NMNA2_HUMAN

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).

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 1-183261260-C-T is Pathogenic according to our data. Variant chr1-183261260-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520701.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NMNAT2	NM_015039.4 link	c.695G>A	p.Arg232Gln	missense_variant	Exon 9 of 11	ENST00000287713.7	NP_055854.1	Q9BZQ4-1
NMNAT2	NM_170706.4 link	c.680G>A	p.Arg227Gln	missense_variant	Exon 9 of 11		NP_733820.1	Q9BZQ4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NMNAT2	ENST00000287713.7 link	c.695G>A	p.Arg232Gln	missense_variant	Exon 9 of 11	1	NM_015039.4	ENSP00000287713.6	Q9BZQ4-1
NMNAT2	ENST00000294868.8 link	c.680G>A	p.Arg227Gln	missense_variant	Exon 9 of 11	1		ENSP00000294868.4	Q9BZQ4-2
NMNAT2	ENST00000464047.1 link	n.177G>A		non_coding_transcript_exon_variant	Exon 2 of 4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251452

AF XY:

0.00000736

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1112002

Other (OTH)

AF:

0.0000166

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Pathogenic:1

Jul 29, 2021

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.695G>A (p.R232Q) alteration is located in exon 9 of the NMNAT2 gene. This alteration results from a G to A substitution at nucleotide position 695, causing the arginine (R) at amino acid position 232 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (3/251452) total alleles studied. The highest observed frequency was <0.01% (3/113734) of European (non-Finnish) alleles. This amino acid position is highly conserved in available vertebrate species. The p.R232 amino acid is located in the NAD binding pocket of the NMNAT2 enzyme and is found to be crucial for the function of the protein due to its direct interaction with NAD. Homology modeling of this amino acid alteration conducted internally at Ambry Genetics using the published crystal structure of the homologous NMNAT3 protein (Zhang, 2003) indicated that this alteration would disrupt the interaction of NMNAT2 with NAD and thereby its function in the biosynthesis of NAD. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

.;D

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

.;M

PhyloP100

7.6

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.035

D;D

Polyphen

1.0

D;D

Vest4

0.99

MutPred

0.88

.;Gain of catalytic residue at R232 (P = 0.0687);

MVP

0.99

MPC

2.1

ClinPred

1.0

GERP RS

5.4

Varity_R

0.82

gMVP

0.96

Mutation Taster

=37/63

disease causing (ClinVar)

(source)

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

Publications

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1-183261260-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over