chr21-38818503-C-T

Variant names:

• chr21-38818503-C-T
• rs114562289
• NM_005239.6:c.668C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005239.6(ETS2):​c.668C>T​(p.Pro223Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000396 in 1,614,138 control chromosomes in the GnomAD database, including 2 homozygotes. 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: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: ETS2 NM_005239.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020874202).
• BS2: High AC in GnomAd4 at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETS2	NM_005239.6	c.668C>T	p.Pro223Leu	missense_variant	Exon 7 of 10	ENST00000360938.8	NP_005230.1
ETS2	NM_001256295.2	c.1088C>T	p.Pro363Leu	missense_variant	Exon 8 of 11		NP_001243224.1
ETS2	XM_005260935.2	c.668C>T	p.Pro223Leu	missense_variant	Exon 7 of 10		XP_005260992.1
ETS2	XM_017028290.2	c.668C>T	p.Pro223Leu	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.668C>T	p.Pro223Leu	missense_variant	Exon 7 of 10	1	NM_005239.6	ENSP00000354194.3

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000509 AC: 128 AN: 251452 Hom.: 2 AF XY: 0.000419 AC XY: 57 AN XY: 135906

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000391 AC: 572 AN: 1461888 Hom.: 2 Cov.: 32 AF XY: 0.000380 AC XY: 276 AN XY: 727248

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.000974

Gnomad4 NFE exome AF: 0.000362

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74450

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000755

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000363 Hom.: 0

Bravo AF: 0.000502

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000379 AC: 46

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 21, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.668C>T (p.P223L) alteration is located in exon 7 (coding exon 6) of the ETS2 gene. This alteration results from a C to T substitution at nucleotide position 668, causing the proline (P) at amino acid position 223 to be replaced by a leucine (L). 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	0.066
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Uncertain	0.50	T;T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.83	T;.;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.021	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.067
Sift	Uncertain	0.010	D;D;D
Sift4G	Benign	0.13	T;T;D
Polyphen		0.22	B;B;B
Vest4		0.31
MVP		0.27
MPC		0.32
ClinPred		0.036	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.53

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: rs114562289; hg19: chr21-40190427;