rs768849266

Variant names:

• chr1-183261260-C-T
• rs768849266
• NM_015039.4:c.695G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.60
• Publications: 9 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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 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).
• 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 VariationId is 520701.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015039.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NMNAT2	NM_015039.4	MANE Select	c.695G>A	p.Arg232Gln	missense	Exon 9 of 11	NP_055854.1	Q9BZQ4-1
	NMNAT2	NM_170706.4		c.680G>A	p.Arg227Gln	missense	Exon 9 of 11	NP_733820.1	Q9BZQ4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NMNAT2	ENST00000287713.7	TSL:1 MANE Select	c.695G>A	p.Arg232Gln	missense	Exon 9 of 11	ENSP00000287713.6	Q9BZQ4-1
	NMNAT2	ENST00000294868.8	TSL:1	c.680G>A	p.Arg227Gln	missense	Exon 9 of 11	ENSP00000294868.4	Q9BZQ4-2
	NMNAT2	ENST00000918147.1		c.569G>A	p.Arg190Gln	missense	Exon 7 of 9	ENSP00000588206.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251452 AF XY: 0.00000736

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: 18 AN: 1461708 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727176

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60376

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	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	D
GERP RS		5.4
Varity_R		0.82
gMVP		0.96
Mutation Taster		=37/63	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs768849266; hg19: chr1-183230395; COSMIC: COSV54271412;