9-34343180-GA-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001161.5(NUDT2):c.186delA(p.Ala63GlnfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

NUDT2
NM_001161.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 9.08

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.581 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-34343180-GA-G is Pathogenic according to our data. Variant chr9-34343180-GA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 689658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-34343180-GA-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT2	NM_001161.5 link	c.186delA	p.Ala63GlnfsTer3	frameshift_variant	Exon 5 of 5	ENST00000379158.7	NP_001152.1	P50583
NUDT2	NM_001244390.2 link	c.186delA	p.Ala63GlnfsTer3	frameshift_variant	Exon 3 of 3		NP_001231319.1	P50583
NUDT2	NM_147172.3 link	c.186delA	p.Ala63GlnfsTer3	frameshift_variant	Exon 5 of 5		NP_671701.1	P50583
NUDT2	NM_147173.3 link	c.186delA	p.Ala63GlnfsTer3	frameshift_variant	Exon 4 of 4		NP_671702.1	P50583

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NUDT2	ENST00000379158.7 link	c.186delA	p.Ala63GlnfsTer3	frameshift_variant	Exon 5 of 5	3	NM_001161.5	ENSP00000368455.1	P50583
NUDT2	ENST00000346365.8 link	c.186delA	p.Ala63GlnfsTer3	frameshift_variant	Exon 4 of 4	1		ENSP00000344187.4	P50583
NUDT2	ENST00000379155.9 link	c.186delA	p.Ala63GlnfsTer3	frameshift_variant	Exon 5 of 5	3		ENSP00000368452.5	P50583
NUDT2	ENST00000618590.1 link	c.186delA	p.Ala63GlnfsTer3	frameshift_variant	Exon 3 of 3	3		ENSP00000482384.1	P50583

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251412

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000293

AC:

428

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000281

AC XY:

204

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000112

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:

0.000368

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000131

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000151

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual developmental disorder with or without peripheral neuropathy

Pathogenic:3

Mar 14, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000689658 /PMID: 31607746). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Mar 28, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NUDT2 c.186delA (p.Ala63GlnfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein, however current evidence is not sufficient to establish loss-of-function variants in NUDT2 as causative of disease. The variant allele was found at a frequency of 0.00012 in 251412 control chromosomes (gnomAD). c.186delA has been reported in the literature in individuals affected with Intellectual Developmental with Neuropathy (Diaz_2020). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 33058507). ClinVar contains an entry for this variant (Variation ID: 689658). Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 16, 2025

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:3

May 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ala63Glnfs*3) in the NUDT2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 85 amino acid(s) of the NUDT2 protein. This variant is present in population databases (rs529087882, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with NUDT2-related conditions (PMID: 33058507). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 689658). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jan 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 16, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 85 amino acids are replaced with 2 different amino acids; This variant is associated with the following publications: (PMID: 31607746, 33058507, 38243213) -

Intellectual disability

Pathogenic:1

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Complex neurodevelopmental disorder

Pathogenic:1

Apr 22, 2022

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is a deletion of 1 bp in exon 5 (of 5) of NUDT2 that is predicted to create a premature termination codon at position 65, p.(Ala63Glnfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to remove the last 83 amino acids (greater than half of the protein). Loss of function has recently been established as a mechanism of disease for this gene (PMID: 27431290, 30059600, 33058507). The variant is present in a large population cohort at a frequency of 0.01% (29/251,412 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified in the homozygous state in two unrelated individuals with intellectual disability and polyneuropathy, and segregates to a similarly affected sibling in one of these families (PMID: 33058507). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PM2, PM3, PP1. -

NUDT2-associated condition

Pathogenic:1

Jul 30, 2019

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over