chr21-38818456-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005239.6(ETS2):​c.621G>A​(p.Met207Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

ETS2
NM_005239.6 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.43
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-AS1 (HGNC:56712): (ETS2 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.09504786).
BS2
High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ETS2NM_005239.6 linkuse as main transcriptc.621G>A p.Met207Ile missense_variant 7/10 ENST00000360938.8 NP_005230.1
ETS2NM_001256295.2 linkuse as main transcriptc.1041G>A p.Met347Ile missense_variant 8/11 NP_001243224.1
ETS2XM_005260935.2 linkuse as main transcriptc.621G>A p.Met207Ile missense_variant 7/10 XP_005260992.1
ETS2XM_017028290.2 linkuse as main transcriptc.621G>A p.Met207Ile missense_variant 7/10 XP_016883779.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ETS2ENST00000360938.8 linkuse as main transcriptc.621G>A p.Met207Ile missense_variant 7/101 NM_005239.6 ENSP00000354194 P1
ETS2-AS1ENST00000663561.1 linkuse as main transcriptn.535-5031C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251160
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135814
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461862
Hom.:
0
Cov.:
32
AF XY:
0.00000825
AC XY:
6
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000617
Hom.:
0
Bravo
AF:
0.00000378
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 03, 2022The c.621G>A (p.M207I) alteration is located in exon 7 (coding exon 6) of the ETS2 gene. This alteration results from a G to A substitution at nucleotide position 621, causing the methionine (M) at amino acid position 207 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
8.4
DANN
Benign
0.74
DEOGEN2
Benign
0.33
T;T;T
Eigen
Benign
-0.90
Eigen_PC
Benign
-0.79
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.56
T;.;T
M_CAP
Benign
0.0047
T
MetaRNN
Benign
0.095
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.7
L;L;.
MutationTaster
Benign
0.94
N;N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.10
N;N;N
REVEL
Benign
0.091
Sift
Benign
0.47
T;T;T
Sift4G
Benign
0.48
T;T;T
Polyphen
0.0
B;B;B
Vest4
0.19
MutPred
0.38
Loss of disorder (P = 0.0642);Loss of disorder (P = 0.0642);Loss of disorder (P = 0.0642);
MVP
0.33
MPC
0.35
ClinPred
0.020
T
GERP RS
2.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.047
gMVP
0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs981053782; hg19: chr21-40190380; COSMIC: COSV62872936; COSMIC: COSV62872936; API