21-38814822-C-T

Variant names:

• chr21-38814822-C-T
• rs78391361
• NM_005239.6:c.346C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005239.6(ETS2):​c.346C>T​(p.Leu116Phe) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ETS2 NM_005239.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.409
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010845423).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETS2	NM_005239.6	c.346C>T	p.Leu116Phe	missense_variant	Exon 5 of 10	ENST00000360938.8	NP_005230.1
ETS2	NM_001256295.2	c.766C>T	p.Leu256Phe	missense_variant	Exon 6 of 11		NP_001243224.1
ETS2	XM_005260935.2	c.346C>T	p.Leu116Phe	missense_variant	Exon 5 of 10		XP_005260992.1
ETS2	XM_017028290.2	c.346C>T	p.Leu116Phe	missense_variant	Exon 5 of 10		XP_016883779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETS2	ENST00000360938.8	c.346C>T	p.Leu116Phe	missense_variant	Exon 5 of 10	1	NM_005239.6	ENSP00000354194.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00217 AC: 541 AN: 248964 AF XY: 0.00140

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.000767

Gnomad FIN exome AF: 0.00361

Gnomad NFE exome AF: 0.00209

Gnomad OTH exome AF: 0.00315

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000179 AC: 262 AN: 1460984 Hom.: 0 Cov.: 32 AF XY: 0.000195 AC XY: 142 AN XY: 726808

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00387 AC: 204 AN: 52768

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111880

Other (OTH) AF: 0.000531 AC: 32 AN: 60280

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0135 AC: 1642

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.33	T;T;.;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.70	T;.;T;T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L;.;.
PhyloP100		0.41
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.75	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.66	T;T;T;T
Sift4G	Benign	0.71	T;T;T;T
Polyphen		0.0010	B;B;.;B
Vest4		0.094
MPC		0.34
ClinPred		0.0032	T
GERP RS		4.1
Varity_R		0.16
gMVP		0.34
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs78391361; hg19: chr21-40186746;