9-34343180-GA-G

Position:

chr9-34343180-GA-G

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.Ala63fs) 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:8

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:

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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/exons	MANE	Protein	UniProt
NUDT2	NM_001161.5 linkuse as main transcript	c.186delA	p.Ala63fs	frameshift_variant	5/5	ENST00000379158.7	NP_001152.1	P50583
NUDT2	NM_001244390.2 linkuse as main transcript	c.186delA	p.Ala63fs	frameshift_variant	3/3		NP_001231319.1	P50583
NUDT2	NM_147172.3 linkuse as main transcript	c.186delA	p.Ala63fs	frameshift_variant	5/5		NP_671701.1	P50583
NUDT2	NM_147173.3 linkuse as main transcript	c.186delA	p.Ala63fs	frameshift_variant	4/4		NP_671702.1	P50583

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NUDT2	ENST00000379158.7 linkuse as main transcript	c.186delA	p.Ala63fs	frameshift_variant	5/5	3	NM_001161.5	ENSP00000368455.1	P50583
NUDT2	ENST00000346365.8 linkuse as main transcript	c.186delA	p.Ala63fs	frameshift_variant	4/4	1		ENSP00000344187.4	P50583
NUDT2	ENST00000379155.9 linkuse as main transcript	c.186delA	p.Ala63fs	frameshift_variant	5/5	3		ENSP00000368452.5	P50583
NUDT2	ENST00000618590.1 linkuse as main transcript	c.186delA	p.Ala63fs	frameshift_variant	3/3	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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2024	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 03, 2023	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. ClinVar contains an entry for this variant (Variation ID: 689658). 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. This variant is present in population databases (rs529087882, gnomAD 0.02%). 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. -

Intellectual developmental disorder with or without peripheral neuropathy

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2024	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. -

Intellectual disability

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

- -

NUDT2-associated condition

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Jul 30, 2019

- -

Complex neurodevelopmental disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Apr 22, 2022

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. -

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