rs775006132

Variant names:

• chr10-103091603-T-C
• rs775006132
• NM_001351169.2:c.1172A>G

Variant summary

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

The NM_001351169.2(NT5C2):​c.1172A>G​(p.Glu391Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,188 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NT5C2 NM_001351169.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NT5C2	NM_001351169.2	c.1172A>G	p.Glu391Gly	missense_variant	Exon 16 of 19	ENST00000404739.8	NP_001338098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NT5C2	ENST00000404739.8	c.1172A>G	p.Glu391Gly	missense_variant	Exon 16 of 19	1	NM_001351169.2	ENSP00000383960.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251348 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461188 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1172A>G (p.E391G) alteration is located in exon 1 (coding exon 1) of the NT5C2 gene. This alteration results from a A to G substitution at nucleotide position 1172, causing the glutamic acid (E) at amino acid position 391 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia 45 Uncertain:1

Feb 07, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with glycine at codon 391 of the NT5C2 protein (p.Glu391Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. The frequency data for this variant (rs775006132) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a NT5C2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, this variant is a missense change with unknown frequency in the general population and with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T;T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.010	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.89
MutPred		0.55		Loss of stability (P = 0.0051);Loss of stability (P = 0.0051);.;
MVP		0.58
MPC		1.2
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.55
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs775006132; hg19: chr10-104851360; COSMIC: COSV58415905; COSMIC: COSV58415905;