rs537259520
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP3BS1_Supporting
The NM_001351169.2(NT5C2):βc.1674_1679delβ(p.Glu559_Glu560del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,559,886 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.00012 ( 0 hom., cov: 32)
Exomes π: 0.00017 ( 1 hom. )
Consequence
NT5C2
NM_001351169.2 inframe_deletion
NM_001351169.2 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.29
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]
CNNM2 (HGNC:103): (cyclin and CBS domain divalent metal cation transport mediator 2) This gene encodes a member of the ancient conserved domain containing protein family. Members of this protein family contain a cyclin box motif and have structural similarity to the cyclins. The encoded protein may play an important role in magnesium homeostasis by mediating the epithelial transport and renal reabsorption of Mg2+. Mutations in this gene are associated with renal hypomagnesemia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP3
Nonframeshift variant in repetitive region in NM_001351169.2
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000173 (243/1407852) while in subpopulation NFE AF= 0.000191 (205/1073650). AF 95% confidence interval is 0.000169. There are 1 homozygotes in gnomad4_exome. There are 119 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NT5C2 | NM_001351169.2 | c.1674_1679del | p.Glu559_Glu560del | inframe_deletion | 19/19 | ENST00000404739.8 | NP_001338098.1 | |
| CNNM2 | NM_017649.5 | c.*12510_*12515del | 3_prime_UTR_variant | 8/8 | ENST00000369878.9 | NP_060119.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NT5C2 | ENST00000404739.8 | c.1674_1679del | p.Glu559_Glu560del | inframe_deletion | 19/19 | 1 | NM_001351169.2 | ENSP00000383960 | P1 | |
| CNNM2 | ENST00000369878.9 | c.*12510_*12515del | 3_prime_UTR_variant | 8/8 | 1 | NM_017649.5 | ENSP00000358894 | P4 |
Frequencies
GnomAD3 genomes 0.000125 AC: 19AN: 152034Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000118 AC: 26AN: 220626Hom.: 0 AF XY: 0.000118 AC XY: 14AN XY: 118498
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GnomAD4 exome AF: 0.000173 AC: 243AN: 1407852Hom.: 1 AF XY: 0.000170 AC XY: 119AN XY: 699650
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GnomAD4 genome 0.000125 AC: 19AN: 152034Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74260
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jun 14, 2018 | - - |
Hereditary spastic paraplegia 45 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 27, 2022 | This sequence change creates a premature translational stop signal (p.Glu560*) in the NT5C2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acid(s) of the NT5C2 protein. This variant is present in population databases (rs763843500, gnomAD 0.03%). 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: 474945). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at