rs763305896
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001351169.2(NT5C2):βc.312_313delβ(p.Leu105ValfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,554 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 6.8e-7 ( 0 hom. )
Consequence
NT5C2
NM_001351169.2 frameshift
NM_001351169.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.94
Genes affected
NT5C2 (HGNC:8022): (5'-nucleotidase, cytosolic II) This gene encodes a hydrolase that serves as an important role in cellular purine metabolism by acting primarily on inosine 5'-monophosphate and other purine nucleotides. [provided by RefSeq, Oct 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 10-103105781-AGT-A is Pathogenic according to our data. Variant chr10-103105781-AGT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 541762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NT5C2 | NM_001351169.2 | c.312_313del | p.Leu105ValfsTer21 | frameshift_variant | 6/19 | ENST00000404739.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NT5C2 | ENST00000404739.8 | c.312_313del | p.Leu105ValfsTer21 | frameshift_variant | 6/19 | 1 | NM_001351169.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250936Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135640
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460356Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726568
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 45 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Leu105Valfs*21) in the NT5C2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NT5C2 are known to be pathogenic (PMID: 24482476). This variant is present in population databases (rs763305896, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with NT5C2-related conditions. ClinVar contains an entry for this variant (Variation ID: 541762). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Feb 16, 2022 | PVS1, PM2 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 13, 2022 | Variant summary: NT5C2 c.312_313delAC (p.Leu105ValfsX21) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in HGMD in association with Spastic paraplegia. The variant allele was found at a frequency of 8e-06 in 250936 control chromosomes. To our knowledge, no occurrence of c.312_313delAC in individuals affected with Hereditary Spastic Paraplegia 45 and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at