9-34343283-C-G

Variant names:

• chr9-34343283-C-G
• rs200364521
• NM_001161.5:c.287C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001161.5(NUDT2):​c.287C>G​(p.Ala96Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A96V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NUDT2 NM_001161.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.70
• Publications: 7 publications found

Genes affected

NUDT2 (HGNC:8049): (nudix hydrolase 2) This gene encodes a member of the MutT family of nucleotide pyrophosphatases, a subset of the larger NUDIX hydrolase family. The gene product possesses a modification of the MutT sequence motif found in certain nucleotide pyrophosphatases. The enzyme asymmetrically hydrolyzes Ap4A to yield AMP and ATP and is responsible for maintaining the intracellular level of the dinucleotide Ap4A, the function of which has yet to be established. This gene may be a candidate tumor suppressor gene. Alternative splicing has been observed at this locus and four transcript variants, all encoding the same protein, have been identified. [provided by RefSeq, Sep 2011]

NUDT2 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with or without peripheral neuropathy

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 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: 0.48454 (below the threshold of 3.09). Trascript score misZ: 0.46602 (below the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder with or without peripheral neuropathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010906637).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001161.5. 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
	NUDT2	NM_001161.5	MANE Select	c.287C>G	p.Ala96Gly	missense	Exon 5 of 5	NP_001152.1	P50583
	NUDT2	NM_001244390.2		c.287C>G	p.Ala96Gly	missense	Exon 3 of 3	NP_001231319.1	P50583
	NUDT2	NM_147172.3		c.287C>G	p.Ala96Gly	missense	Exon 5 of 5	NP_671701.1	P50583

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUDT2	ENST00000379158.7	TSL:3 MANE Select	c.287C>G	p.Ala96Gly	missense	Exon 5 of 5	ENSP00000368455.1	P50583
	NUDT2	ENST00000346365.9	TSL:1	c.287C>G	p.Ala96Gly	missense	Exon 4 of 4	ENSP00000344187.4	P50583
	NUDT2	ENST00000379155.9	TSL:3	c.287C>G	p.Ala96Gly	missense	Exon 5 of 5	ENSP00000368452.5	P50583

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00218 AC: 529 AN: 243112 AF XY: 0.00164

Gnomad AFR exome AF: 0.00569

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.000910

Gnomad EAS exome AF: 0.00129

Gnomad FIN exome AF: 0.00110

Gnomad NFE exome AF: 0.00329

Gnomad OTH exome AF: 0.00373

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000138 AC: 202 AN: 1458492 Hom.: 0 Cov.: 31 AF XY: 0.000159 AC XY: 115 AN XY: 725508

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000896 AC: 3 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39516

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00221 AC: 114 AN: 51552

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5718

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1111196

Other (OTH) AF: 0.000299 AC: 18 AN: 60120

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00971 AC: 1151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.055	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.7
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.37
Sift	Benign	0.033	D
Sift4G	Benign	0.11	T
Polyphen		0.97	D
Vest4		0.71
MVP		0.37
MPC		1.3
ClinPred		0.027	T
GERP RS		5.9
Varity_R		0.62
gMVP		0.77
Mutation Taster		=29/71	disease causing

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: rs200364521; hg19: chr9-34343281; COSMIC: COSV60678523;