21-38814811-G-A

Position:

• chr21-38814811-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005239.6(ETS2):​c.335G>A​(p.Cys112Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ETS2 NM_005239.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18

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]

ENSG00000205622 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17101753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETS2	NM_005239.6	c.335G>A	p.Cys112Tyr	missense_variant	5/10	ENST00000360938.8	NP_005230.1
ETS2	NM_001256295.2	c.755G>A	p.Cys252Tyr	missense_variant	6/11		NP_001243224.1
ETS2	XM_005260935.2	c.335G>A	p.Cys112Tyr	missense_variant	5/10		XP_005260992.1
ETS2	XM_017028290.2	c.335G>A	p.Cys112Tyr	missense_variant	5/10		XP_016883779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETS2	ENST00000360938.8	c.335G>A	p.Cys112Tyr	missense_variant	5/10	1	NM_005239.6	ENSP00000354194.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2023

The c.335G>A (p.C112Y) alteration is located in exon 5 (coding exon 4) of the ETS2 gene. This alteration results from a G to A substitution at nucleotide position 335, causing the cysteine (C) at amino acid position 112 to be replaced by a tyrosine (Y). 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	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Benign	0.48
DEOGEN2	Benign	0.38	T;T;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T;.;T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;.;.
MutationTaster	Benign	0.77	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.091
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.48
MutPred		0.68		Gain of MoRF binding (P = 0.2027);Gain of MoRF binding (P = 0.2027);Gain of MoRF binding (P = 0.2027);Gain of MoRF binding (P = 0.2027);
MVP		0.30
MPC		0.55
ClinPred		0.14	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.68

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

Other links and lift over

dbSNP: rs2060926543; hg19: chr21-40186735;