9-34343293-G-C

Variant names:

• chr9-34343293-G-C
• rs1432136565
• NM_001161.5:c.297G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001161.5(NUDT2):​c.297G>C​(p.Lys99Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,611,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NUDT2 NM_001161.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.353

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1578469).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT2	NM_001161.5	c.297G>C	p.Lys99Asn	missense_variant	Exon 5 of 5	ENST00000379158.7	NP_001152.1
NUDT2	NM_001244390.2	c.297G>C	p.Lys99Asn	missense_variant	Exon 3 of 3		NP_001231319.1
NUDT2	NM_147172.3	c.297G>C	p.Lys99Asn	missense_variant	Exon 5 of 5		NP_671701.1
NUDT2	NM_147173.3	c.297G>C	p.Lys99Asn	missense_variant	Exon 4 of 4		NP_671702.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUDT2	ENST00000379158.7	c.297G>C	p.Lys99Asn	missense_variant	Exon 5 of 5	3	NM_001161.5	ENSP00000368455.1
NUDT2	ENST00000346365.8	c.297G>C	p.Lys99Asn	missense_variant	Exon 4 of 4	1		ENSP00000344187.4
NUDT2	ENST00000379155.9	c.297G>C	p.Lys99Asn	missense_variant	Exon 5 of 5	3		ENSP00000368452.5
NUDT2	ENST00000618590.1	c.297G>C	p.Lys99Asn	missense_variant	Exon 3 of 3	3		ENSP00000482384.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459698 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726158

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.297G>C (p.K99N) alteration is located in exon 5 (coding exon 2) of the NUDT2 gene. This alteration results from a G to C substitution at nucleotide position 297, causing the lysine (K) at amino acid position 99 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	T;T;T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	.;.;T;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	L;L;L;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.9	N;N;.;N
REVEL	Benign	0.079
Sift	Benign	0.38	T;T;.;T
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.024	B;B;B;B
Vest4		0.17
MutPred		0.50		Loss of ubiquitination at K99 (P = 0.0244);Loss of ubiquitination at K99 (P = 0.0244);Loss of ubiquitination at K99 (P = 0.0244);Loss of ubiquitination at K99 (P = 0.0244);
MVP		0.24
MPC		0.77
ClinPred		0.25	T
GERP RS		1.2
Varity_R		0.40
gMVP		0.52

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

LitVar

Other links and lift over

dbSNP: rs1432136565; hg19: chr9-34343291;