rs200971953

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_001127208.3(TET2):c.5885C>T(p.Pro1962Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000523 in 1,551,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00054 ( 0 hom. )

Consequence

TET2
NM_001127208.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O:1

Conservation

PhyloP100: 4.57

Publications

16 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2392289).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000362 (55/152080) while in subpopulation NFE AF = 0.000632 (43/68006). AF 95% confidence interval is 0.000482. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TET2	NM_001127208.3 link	c.5885C>T	p.Pro1962Leu	missense_variant	Exon 11 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.5885C>T	p.Pro1962Leu	missense_variant	Exon 11 of 11	5	NM_001127208.3	ENSP00000369351.4		Q6N021-1

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000632

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000215

AC:

AN:

157912

AF XY:

0.000252

show subpopulations

Gnomad AFR exome

AF:

0.000122

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000591

Gnomad NFE exome

AF:

0.000521

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000541

AC:

757

AN:

1399710

Hom.:

Cov.:

AF XY:

0.000532

AC XY:

367

AN XY:

690338

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31600

American (AMR)

AF:

0.00

AC:

AN:

35706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.000121

AC:

AN:

49422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.000669

AC:

722

AN:

1079040

Other (OTH)

AF:

0.000465

AC:

AN:

58086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<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:

0.000362

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.000431

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.000242

AC:

AN:

41404

American (AMR)

AF:

0.000131

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000632

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

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:

0.000250

Hom.:

Bravo

AF:

0.000325

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000314

AC:

ExAC

AF:

0.0000391

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TET2: PM2:Supporting, BP4 -

Jan 16, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4 -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1962 of the TET2 protein (p.Pro1962Leu). This variant is present in population databases (rs200971953, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of acute myeloid leukemia or myelodysplastic syndrome (PMID: 22116554, 22390313, 32098966). ClinVar contains an entry for this variant (Variation ID: 135294). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

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

0.27

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

D;D;.

M_CAP

Benign

0.036

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

.;M;M

PhyloP100

4.6

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-4.9

D;D;D

REVEL

Benign

0.20

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.016

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.29

MVP

0.60

MPC

0.36

ClinPred

0.63

GERP RS

4.7

Varity_R

0.22

gMVP

0.44

Mutation Taster

=75/25

polymorphism

(source)

Splicing

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