NM_005239.6:c.680C>G

Variant names:

• chr21-38818515-C-G
• NM_005239.6:c.680C>G

Variant summary

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

The NM_005239.6(ETS2):​c.680C>G​(p.Pro227Arg) 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. 13/21 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)
• Consequence: ETS2 NM_005239.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51

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:56712): (ETS2 antisense RNA 1)

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=0.12872723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETS2	NM_005239.6	c.680C>G	p.Pro227Arg	missense_variant	Exon 7 of 10	ENST00000360938.8	NP_005230.1
ETS2	NM_001256295.2	c.1100C>G	p.Pro367Arg	missense_variant	Exon 8 of 11		NP_001243224.1
ETS2	XM_005260935.2	c.680C>G	p.Pro227Arg	missense_variant	Exon 7 of 10		XP_005260992.1
ETS2	XM_017028290.2	c.680C>G	p.Pro227Arg	missense_variant	Exon 7 of 10		XP_016883779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETS2	ENST00000360938.8	c.680C>G	p.Pro227Arg	missense_variant	Exon 7 of 10	1	NM_005239.6	ENSP00000354194.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.680C>G (p.P227R) alteration is located in exon 7 (coding exon 6) of the ETS2 gene. This alteration results from a C to G substitution at nucleotide position 680, causing the proline (P) at amino acid position 227 to be replaced by an arginine (R). 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	0.10
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	D;D;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.45	T;.;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.0	M;M;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.032	D;D;D
Sift4G	Benign	0.35	T;T;T
Polyphen		0.10	B;B;B
Vest4		0.61
MutPred		0.18		Gain of catalytic residue at P227 (P = 0.0353);Gain of catalytic residue at P227 (P = 0.0353);Gain of catalytic residue at P227 (P = 0.0353);
MVP		0.37
MPC		0.44
ClinPred		0.24	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-40190439;