21-38818484-C-A

Position:

• chr21-38818484-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005239.6(ETS2):​c.649C>A​(p.Leu217Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00933 in 1,614,172 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (91 hom.)
• Consequence: ETS2 NM_005239.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.59

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005959183).
• BP6: Variant 21-38818484-C-A is Benign according to our data. Variant chr21-38818484-C-A is described in ClinVar as [Benign]. Clinvar id is 780076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1214 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETS2	NM_005239.6	c.649C>A	p.Leu217Ile	missense_variant	7/10	ENST00000360938.8	NP_005230.1
ETS2	NM_001256295.2	c.1069C>A	p.Leu357Ile	missense_variant	8/11		NP_001243224.1
ETS2	XM_005260935.2	c.649C>A	p.Leu217Ile	missense_variant	7/10		XP_005260992.1
ETS2	XM_017028290.2	c.649C>A	p.Leu217Ile	missense_variant	7/10		XP_016883779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETS2	ENST00000360938.8	c.649C>A	p.Leu217Ile	missense_variant	7/10	1	NM_005239.6	ENSP00000354194	P1
ETS2-AS1	ENST00000663561.1	n.535-5059G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00798 AC: 1215 AN: 152172 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.00735 AC: 1848 AN: 251382 Hom.: 14 AF XY: 0.00730 AC XY: 992 AN XY: 135882

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00590

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00831

GnomAD4 exome AF: 0.00947 AC: 13848 AN: 1461882 Hom.: 91 Cov.: 32 AF XY: 0.00918 AC XY: 6676 AN XY: 727246

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00610

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.00344

Gnomad4 NFE exome AF: 0.0109

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00797 AC: 1214 AN: 152290 Hom.: 9 Cov.: 32 AF XY: 0.00739 AC XY: 550 AN XY: 74462

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00752

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.0109 Hom.: 4

Bravo AF: 0.00876

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.00726 AC: 882

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0134

EpiControl AF: 0.0132

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ETS2: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;T;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.65	T;.;T
MetaRNN	Benign	0.0060	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.36	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.58	T;T;D
Sift4G	Benign	0.34	T;T;T
Polyphen		0.91	P;P;D
Vest4		0.40
MVP		0.47
MPC		0.35
ClinPred		0.019	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.082
gMVP		0.58

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: rs61735785; hg19: chr21-40190408;