rs6843141

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001127208.3(TET2):c.652G>A(p.Val218Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,613,946 control chromosomes in the GnomAD database, including 4,268 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V218E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.10 ( 1907 hom., cov: 33)

Exomes 𝑓: 0.032 ( 2361 hom. )

Consequence

TET2
NM_001127208.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 0.755

Publications

45 publications found

Variant links:

Genes affected

TET2 (HGNC:25941): (tet methylcytosine dioxygenase 2) The protein encoded by this gene is a methylcytosine dioxygenase that catalyzes the conversion of methylcytosine to 5-hydroxymethylcytosine. The encoded protein is involved in myelopoiesis, and defects in this gene have been associated with several myeloproliferative disorders. Two variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

TET2 links:

TET2-AS1 (HGNC:41125): (TET2 antisense RNA 1)

TET2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022783577).

BP6

Variant 4-105234594-G-A is Benign according to our data. Variant chr4-105234594-G-A is described in ClinVar as Benign. ClinVar VariationId is 135321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TET2	NM_001127208.3 link	c.652G>A	p.Val218Met	missense_variant	Exon 3 of 11	ENST00000380013.9	NP_001120680.1	Q6N021-1A0A158SIU0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TET2	ENST00000380013.9 link	c.652G>A	p.Val218Met	missense_variant	Exon 3 of 11	5	NM_001127208.3	ENSP00000369351.4		Q6N021-1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15865

AN:

152066

Hom.:

1899

Cov.:

show subpopulations

Gnomad AFR

AF:

0.291

Gnomad AMI

AF:

0.0264

Gnomad AMR

AF:

0.0475

Gnomad ASJ

AF:

0.0544

Gnomad EAS

AF:

0.0665

Gnomad SAS

AF:

0.0422

Gnomad FIN

AF:

0.0663

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0212

Gnomad OTH

AF:

0.0891

GnomAD2 exomes

AF:

0.0511

AC:

12812

AN:

250900

AF XY:

0.0466

show subpopulations

Gnomad AFR exome

AF:

0.293

Gnomad AMR exome

AF:

0.0213

Gnomad ASJ exome

AF:

0.0501

Gnomad EAS exome

AF:

0.0737

Gnomad FIN exome

AF:

0.0693

Gnomad NFE exome

AF:

0.0225

Gnomad OTH exome

AF:

0.0393

GnomAD4 exome

AF:

0.0322

AC:

47041

AN:

1461762

Hom.:

2361

Cov.:

AF XY:

0.0317

AC XY:

23052

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.304

AC:

10189

AN:

33478

American (AMR)

AF:

0.0245

AC:

1097

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0504

AC:

1318

AN:

26134

East Asian (EAS)

AF:

0.0782

AC:

3102

AN:

39676

South Asian (SAS)

AF:

0.0376

AC:

3246

AN:

86252

European-Finnish (FIN)

AF:

0.0638

AC:

3407

AN:

53376

Middle Eastern (MID)

AF:

0.0470

AC:

271

AN:

5768

European-Non Finnish (NFE)

AF:

0.0192

AC:

21379

AN:

1111972

Other (OTH)

AF:

0.0502

AC:

3032

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

2678

5357

8035

10714

13392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1008

2016

3024

4032

5040

<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:

0.105

AC:

15914

AN:

152184

Hom.:

1907

Cov.:

AF XY:

0.105

AC XY:

7790

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.291

AC:

12078

AN:

41494

American (AMR)

AF:

0.0474

AC:

725

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0544

AC:

189

AN:

3472

East Asian (EAS)

AF:

0.0665

AC:

344

AN:

5176

South Asian (SAS)

AF:

0.0421

AC:

203

AN:

4826

European-Finnish (FIN)

AF:

0.0663

AC:

702

AN:

10594

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0212

AC:

1440

AN:

68014

Other (OTH)

AF:

0.0882

AC:

186

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

615

1230

1846

2461

3076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<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:

0.0446

Hom.:

2621

Bravo

AF:

0.111

TwinsUK

AF:

0.0181

AC:

ALSPAC

AF:

0.0228

AC:

ESP6500AA

AF:

0.284

AC:

1253

ESP6500EA

AF:

0.0209

AC:

180

ExAC

AF:

0.0548

AC:

6656

EpiCase

AF:

0.0206

EpiControl

AF:

0.0223

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 11, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

7.5

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.0054

.;T;T;T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.24

T;T;T;.;T

MetaRNN

Benign

0.0023

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.0

N;.;N;N;.

PhyloP100

0.76

PrimateAI

Benign

0.29

PROVEAN

Benign

0.93

N;N;N;N;N

REVEL

Benign

0.051

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

0.14

T;T;T;T;T

Polyphen

0.0020

B;B;B;B;.

Vest4

0.091

MPC

0.070

ClinPred

0.00029

GERP RS

2.4

Varity_R

0.021

gMVP

0.16

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over