dbSNP rs146031219: TET2:p.Pro174His (chr4-105234463-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001127208.3(TET2):c.521C>A(p.Pro174His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,613,938 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 5 hom. )

Consequence

TET2
NM_001127208.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: 0.908

Publications

23 publications found

Variant links:

COSMIC-nc: COSV54426068

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007983297).

BP6

Variant 4-105234463-C-A is Benign according to our data. Variant chr4-105234463-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135315.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00136 (207/152214) while in subpopulation NFE AF = 0.00237 (161/68006). AF 95% confidence interval is 0.00207. There are 1 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127208.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TET2	NM_001127208.3	MANE Select	c.521C>A	p.Pro174His	missense	Exon 3 of 11	NP_001120680.1	Q6N021-1
TET2	NM_017628.4		c.521C>A	p.Pro174His	missense	Exon 3 of 3	NP_060098.3	Q6N021-2
TET2-AS1	NR_126420.1		n.319-56791G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TET2	ENST00000380013.9	TSL:5 MANE Select	c.521C>A	p.Pro174His	missense	Exon 3 of 11	ENSP00000369351.4	Q6N021-1
TET2	ENST00000513237.5	TSL:1	c.584C>A	p.Pro195His	missense	Exon 3 of 11	ENSP00000425443.1	E7EQS8
TET2	ENST00000540549.5	TSL:1	c.521C>A	p.Pro174His	missense	Exon 3 of 11	ENSP00000442788.1	Q6N021-1

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

207

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00237

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00154

AC:

386

AN:

250054

AF XY:

0.00144

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.000696

Gnomad ASJ exome

AF:

0.000798

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00301

Gnomad NFE exome

AF:

0.00243

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00121

AC:

1774

AN:

1461724

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

857

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000895

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.000612

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00339

AC:

181

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00132

AC:

1469

AN:

1111978

Other (OTH)

AF:

0.00108

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

114

227

341

454

568

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00136

AC:

207

AN:

152214

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41520

American (AMR)

AF:

0.000589

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00237

AC:

161

AN:

68006

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00183

Hom.:

Bravo

AF:

0.00110

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00185

AC:

224

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00202

EpiControl

AF:

0.000889

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

TET2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.016

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.69

M_CAP

Benign

0.052

MetaRNN

Benign

0.0080

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

PhyloP100

0.91

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.57

REVEL

Benign

0.064

Sift

Benign

0.032

Sift4G

Benign

0.18

Polyphen

0.25

Vest4

0.10

MVP

0.45

MPC

0.10

ClinPred

0.018

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.057

gMVP

0.11

Mutation Taster

=100/0

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

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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