21-38813003-C-T
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_005239.6(ETS2):c.73C>T(p.Arg25Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000578 in 1,608,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000052 ( 0 hom. )
Consequence
ETS2
NM_005239.6 missense, splice_region
NM_005239.6 missense, splice_region
Scores
6
7
6
Splicing: ADA: 0.9949
2
Clinical Significance
Conservation
PhyloP100: 6.26
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP3
Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, dbscSNV1_ADA, dbscSNV1_RF, Eigen, FATHMM_MKL [when AlphaMissense, max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
BS2
High AC in GnomAd4 at 17 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ETS2 | NM_005239.6 | c.73C>T | p.Arg25Cys | missense_variant, splice_region_variant | 3/10 | ENST00000360938.8 | NP_005230.1 | |
ETS2 | NM_001256295.2 | c.493C>T | p.Arg165Cys | missense_variant, splice_region_variant | 4/11 | NP_001243224.1 | ||
ETS2 | XM_005260935.2 | c.73C>T | p.Arg25Cys | missense_variant, splice_region_variant | 3/10 | XP_005260992.1 | ||
ETS2 | XM_017028290.2 | c.73C>T | p.Arg25Cys | missense_variant, splice_region_variant | 3/10 | XP_016883779.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ETS2 | ENST00000360938.8 | c.73C>T | p.Arg25Cys | missense_variant, splice_region_variant | 3/10 | 1 | NM_005239.6 | ENSP00000354194 | P1 | |
ETS2-AS1 | ENST00000663561.1 | n.957G>A | non_coding_transcript_exon_variant | 3/3 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152158Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251128Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135750
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GnomAD4 exome AF: 0.0000522 AC: 76AN: 1456754Hom.: 0 Cov.: 29 AF XY: 0.0000497 AC XY: 36AN XY: 725012
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GnomAD4 genome AF: 0.000112 AC: 17AN: 152158Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74322
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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 submitter | clinical testing | Ambry Genetics | Oct 26, 2021 | The c.73C>T (p.R25C) alteration is located in exon 3 (coding exon 2) of the ETS2 gene. This alteration results from a C to T substitution at nucleotide position 73, causing the arginine (R) at amino acid position 25 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;D;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;.;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at