10-103089678-TTCCTCC-T

Position:

• chr10-103089678-TTCCTCC-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP3 BS1_Supporting

The NM_001351169.2(NT5C2):​c.1674_1679del​(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 (★★). Synonymous variant affecting the same amino acid position (i.e. E558E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: NT5C2 NM_001351169.2 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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]

ACMG classification

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	UniProt
NT5C2	NM_001351169.2	c.1674_1679del	p.Glu559_Glu560del	inframe_deletion	19/19	ENST00000404739.8
CNNM2	NM_017649.5	c.*12510_*12515del		3_prime_UTR_variant	8/8	ENST00000369878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NT5C2	ENST00000404739.8	c.1674_1679del	p.Glu559_Glu560del	inframe_deletion	19/19	1	NM_001351169.2	P1
CNNM2	ENST00000369878.9	c.*12510_*12515del		3_prime_UTR_variant	8/8	1	NM_017649.5	P4

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000118 AC: 26 AN: 220626 Hom.: 0 AF XY: 0.000118 AC XY: 14 AN XY: 118498

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.0000679

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000162

Gnomad FIN exome AF: 0.000299

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000173 AC: 243 AN: 1407852 Hom.: 1 AF XY: 0.000170 AC XY: 119 AN XY: 699650

Gnomad4 AFR exome AF: 0.0000934

Gnomad4 AMR exome AF: 0.0000709

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.000385

Gnomad4 NFE exome AF: 0.000191

Gnomad4 OTH exome AF: 0.0000344

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152034 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74260

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000727 Hom.: 0

Bravo AF: 0.000136

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

Invitae

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs537259520; hg19: chr10-104849435;