rs141031435

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001351169.2(NT5C2):c.1665G>T(p.Glu555Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000355 in 1,607,780 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 1 hom. )

Consequence

NT5C2
NM_001351169.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.421

Publications

3 publications found

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:

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]

CNNM2 Gene-Disease associations (from GenCC):

hypomagnesemia, seizures, and intellectual disability 1
Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina, ClinGen
renal hypomagnesemia 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
familial primary hypomagnesemia with normocalciuria and normocalcemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CNNM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.052194774).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000138 (21/152018) while in subpopulation NFE AF = 0.000294 (20/68000). AF 95% confidence interval is 0.000194. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001351169.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NT5C2	NM_001351169.2	MANE Select	c.1665G>T	p.Glu555Asp	missense	Exon 19 of 19	NP_001338098.1	P49902-1
CNNM2	NM_017649.5	MANE Select	c.*12513C>A		3_prime_UTR	Exon 8 of 8	NP_060119.3
NT5C2	NM_001351170.2		c.1689G>T	p.Glu563Asp	missense	Exon 19 of 19	NP_001338099.1	A0A6Q8PHP0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NT5C2	ENST00000404739.8	TSL:1 MANE Select	c.1665G>T	p.Glu555Asp	missense	Exon 19 of 19	ENSP00000383960.3	P49902-1
NT5C2	ENST00000343289.9	TSL:1	c.1665G>T	p.Glu555Asp	missense	Exon 18 of 18	ENSP00000339479.5	P49902-1
CNNM2	ENST00000369878.9	TSL:1 MANE Select	c.*12513C>A		3_prime_UTR	Exon 8 of 8	ENSP00000358894.3	Q9H8M5-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000184

AC:

AN:

245124

AF XY:

0.000197

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000387

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.000377

AC:

549

AN:

1455762

Hom.:

Cov.:

AF XY:

0.000366

AC XY:

265

AN XY:

723888

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33278

American (AMR)

AF:

0.0000454

AC:

AN:

44074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25744

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

85224

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.000481

AC:

533

AN:

1108918

Other (OTH)

AF:

0.000216

AC:

AN:

60116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000138

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41376

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000396

Hom.:

Bravo

AF:

0.000204

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000198

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 45 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.13

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.73

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.015

MetaRNN

Benign

0.052

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.92

PhyloP100

0.42

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.91

REVEL

Benign

0.062

Sift

Benign

0.47

Sift4G

Benign

0.29

Polyphen

0.0020

Vest4

0.48

MutPred

0.076

Loss of helix (P = 0.079)

MVP

0.22

MPC

0.62

ClinPred

0.015

GERP RS

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.034

gMVP

0.26

Mutation Taster

=83/17

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over