rs72846108

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_001351169.2(NT5C2):c.141G>C(p.Lys47Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,583,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K47E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

NT5C2
NM_001351169.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.22

Variant links:

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]

NT5C2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000919 (14/152282) while in subpopulation NFE AF= 0.000206 (14/68032). AF 95% confidence interval is 0.000124. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 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 linkuse as main transcript	c.141G>C	p.Lys47Asn	missense_variant	4/19	ENST00000404739.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NT5C2	ENST00000404739.8 linkuse as main transcript	c.141G>C	p.Lys47Asn	missense_variant	4/19	1	NM_001351169.2	P1	P49902-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000129

AC:

AN:

208902

Hom.:

AF XY:

0.000160

AC XY:

AN XY:

112244

show subpopulations

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:

0.000106

Gnomad NFE exome

AF:

0.000251

Gnomad OTH exome

AF:

0.000565

GnomAD4 exome

AF:

0.000171

AC:

245

AN:

1430748

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

123

AN XY:

709292

show subpopulations

Gnomad4 AFR exome

AF:

0.0000307

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:

0.0000779

Gnomad4 NFE exome

AF:

0.000214

Gnomad4 OTH exome

AF:

0.000102

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000636

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000117

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2021

The c.141G>C (p.K47N) alteration is located in exon 1 (coding exon 1) of the NT5C2 gene. This alteration results from a G to C substitution at nucleotide position 141, causing the lysine (K) at amino acid position 47 to be replaced by an asparagine (N). The p.K47N alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia 45

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 943906). This variant has not been reported in the literature in individuals affected with NT5C2-related conditions. This variant is present in population databases (rs72846108, gnomAD 0.03%). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 47 of the NT5C2 protein (p.Lys47Asn). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.37

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.50

D;D

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-4.1

D;D

REVEL

Benign

0.18

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.97

D;D

Vest4

0.89

MutPred

0.51

Loss of methylation at K47 (P = 0.0014);Loss of methylation at K47 (P = 0.0014);

MVP

0.38

MPC

0.94

ClinPred

0.47

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.84

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