Genetic Variant ETS2:p.Leu217Ile (chr21-38818484-C-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_005239.6(ETS2):c.649C>A(p.Leu217Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00933 in 1,614,172 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0095 ( 91 hom. )

Consequence

ETS2
NM_005239.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.59

Publications

7 publications found

Variant links:

Genes affected

ETS2 (HGNC:3489): (ETS proto-oncogene 2, transcription factor) This gene encodes a transcription factor which regulates genes involved in development and apoptosis. The encoded protein is also a protooncogene and shown to be involved in regulation of telomerase. A pseudogene of this gene is located on the X chromosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

ETS2 links:

ETS2-AS1 (HGNC:56712): (ETS2 antisense RNA 1)

ETS2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005959183).

BP6

Variant 21-38818484-C-A is Benign according to our data. Variant chr21-38818484-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 780076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1214 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005239.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETS2	NM_005239.6	MANE Select	c.649C>A	p.Leu217Ile	missense	Exon 7 of 10	NP_005230.1	P15036
	ETS2	NM_001256295.2		c.1069C>A	p.Leu357Ile	missense	Exon 8 of 11	NP_001243224.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ETS2	ENST00000360938.8	TSL:1 MANE Select	c.649C>A	p.Leu217Ile	missense	Exon 7 of 10	ENSP00000354194.3	P15036
ETS2	ENST00000667466.1		c.649C>A	p.Leu217Ile	missense	Exon 7 of 10	ENSP00000499540.1	A0A590UJP9
ETS2	ENST00000968691.1		c.649C>A	p.Leu217Ile	missense	Exon 7 of 10	ENSP00000638750.1

Frequencies

GnomAD3 genomes

AF:

0.00798

AC:

1215

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.0998

Gnomad AMR

AF:

0.00753

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0121

Gnomad OTH

AF:

0.00957

GnomAD2 exomes

AF:

0.00735

AC:

1848

AN:

251382

AF XY:

0.00730

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00590

Gnomad ASJ exome

AF:

0.0149

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00263

Gnomad NFE exome

AF:

0.0117

Gnomad OTH exome

AF:

0.00831

GnomAD4 exome

AF:

0.00947

AC:

13848

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00918

AC XY:

6676

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

33480

American (AMR)

AF:

0.00610

AC:

273

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0137

AC:

359

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00147

AC:

127

AN:

86258

European-Finnish (FIN)

AF:

0.00344

AC:

184

AN:

53412

Middle Eastern (MID)

AF:

0.0128

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0109

AC:

12171

AN:

1112008

Other (OTH)

AF:

0.0102

AC:

615

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

857

1713

2570

3426

4283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

434

868

1302

1736

2170

<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:

0.00797

AC:

1214

AN:

152290

Hom.:

Cov.:

AF XY:

0.00739

AC XY:

550

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

41556

American (AMR)

AF:

0.00752

AC:

115

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0121

AC:

823

AN:

68020

Other (OTH)

AF:

0.00947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

131

196

262

327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0102

Hom.:

Bravo

AF:

0.00876

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.0120

AC:

103

ExAC

AF:

0.00726

AC:

882

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0134

EpiControl

AF:

0.0132

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Benign

0.11

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0060

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.3

PhyloP100

2.6

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.36

REVEL

Benign

0.13

Sift

Benign

0.58

Sift4G

Benign

0.34

Polyphen

0.91

Vest4

0.40

MVP

0.47

MPC

0.35

ClinPred

0.019

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.082

gMVP

0.58

Mutation Taster

=98/2

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