9-34339107-C-T

Variant names:

• chr9-34339107-C-T
• NM_001161.5:c.68C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001161.5(NUDT2):​c.68C>T​(p.Ala23Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUDT2 NM_001161.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.19
• Publications: 0 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: Uncertain_significance. 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=0.06817588).

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.68C>T	p.Ala23Val	missense	Exon 4 of 5	NP_001152.1	P50583
	NUDT2	NM_001244390.2		c.68C>T	p.Ala23Val	missense	Exon 2 of 3	NP_001231319.1	P50583
	NUDT2	NM_147172.3		c.68C>T	p.Ala23Val	missense	Exon 4 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.68C>T	p.Ala23Val	missense	Exon 4 of 5	ENSP00000368455.1	P50583
	NUDT2	ENST00000346365.9	TSL:1	c.68C>T	p.Ala23Val	missense	Exon 3 of 4	ENSP00000344187.4	P50583
	NUDT2	ENST00000379155.9	TSL:3	c.68C>T	p.Ala23Val	missense	Exon 4 of 5	ENSP00000368452.5	P50583

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.93	L
PhyloP100		2.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.088
Sift	Benign	0.34	T
Sift4G	Benign	0.34	T
Polyphen		0.020	B
Vest4		0.16
MutPred		0.42		Gain of ubiquitination at K18 (P = 0.0982)
MVP		0.048
MPC		0.53
ClinPred		0.17	T
GERP RS		4.9
Varity_R		0.15
gMVP		0.52
Mutation Taster		=88/12	polymorphism

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

hg19: chr9-34339105;