21-38814278-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005239.6(ETS2):c.190G>A(p.Ala64Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,613,808 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0084 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (11 hom.)
• Consequence: ETS2 NM_005239.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0690

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)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003026694).
• BP6: Variant 21-38814278-G-A is Benign according to our data. Variant chr21-38814278-G-A is described in ClinVar as [Benign]. Clinvar id is 786688.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0084 (1278/152180) while in subpopulation AFR AF= 0.0251 (1043/41508). AF 95% confidence interval is 0.0239. There are 12 homozygotes in gnomad4. There are 601 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1267 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETS2	NM_005239.6	c.190G>A	p.Ala64Thr	missense_variant	4/10	ENST00000360938.8
ETS2	NM_001256295.2	c.610G>A	p.Ala204Thr	missense_variant	5/11
ETS2	XM_005260935.2	c.190G>A	p.Ala64Thr	missense_variant	4/10
ETS2	XM_017028290.2	c.190G>A	p.Ala64Thr	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETS2	ENST00000360938.8	c.190G>A	p.Ala64Thr	missense_variant	4/10	1	NM_005239.6	P1
ETS2-AS1	ENST00000663561.1	n.535-853C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00833 AC: 1267 AN: 152062 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00305 AC: 767 AN: 251236 Hom.: 8 AF XY: 0.00255 AC XY: 346 AN XY: 135784

Gnomad AFR exome AF: 0.0262

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00266 AC: 3882 AN: 1461628 Hom.: 11 Cov.: 31 AF XY: 0.00250 AC XY: 1817 AN XY: 727130

Gnomad4 AFR exome AF: 0.0226

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000544

Gnomad4 NFE exome AF: 0.00253

Gnomad4 OTH exome AF: 0.00273

GnomAD4 genome AF: 0.00840 AC: 1278 AN: 152180 Hom.: 12 Cov.: 33 AF XY: 0.00808 AC XY: 601 AN XY: 74400

Gnomad4 AFR AF: 0.0251

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00219

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00327 Hom.: 5

Bravo AF: 0.00901

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0243 AC: 107

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00346 AC: 420

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00130

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.93
Dann	Benign	0.79
DEOGEN2	Benign	0.33	T;T;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.67	T;.;T;T
MetaRNN	Benign	0.0030	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.14	N;N;N;N
REVEL	Benign	0.0080
Sift	Benign	0.52	T;T;T;T
Sift4G	Benign	0.57	T;T;T;T
Polyphen		0.0010	B;B;.;B
Vest4		0.024
MVP		0.56
MPC		0.31
ClinPred		0.0030	T
GERP RS		-7.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.013
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs34373350; hg19: chr21-40186202; COSMIC: COSV100711418;