rs2212596

Variant names:

• chr21-38596610-A-C
• rs2212596
• ENST00000398919.6:c.-149-11665T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000398919.6(ERG):​c.-149-11665T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 152,068 control chromosomes in the GnomAD database, including 15,845 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.45 (15845 hom., cov: 33)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0670
• Publications: 11 publications found

Genes affected

ERG (HGNC:3446): (ETS transcription factor ERG) This gene encodes a member of the erythroblast transformation-specific (ETS) family of transcriptions factors. All members of this family are key regulators of embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis. The protein encoded by this gene is mainly expressed in the nucleus. It contains an ETS DNA-binding domain and a PNT (pointed) domain which is implicated in the self-association of chimeric oncoproteins. This protein is required for platelet adhesion to the subendothelium, inducing vascular cell remodeling. It also regulates hematopoesis, and the differentiation and maturation of megakaryocytic cells. This gene is involved in chromosomal translocations, resulting in different fusion gene products, such as TMPSSR2-ERG and NDRG1-ERG in prostate cancer, EWS-ERG in Ewing's sarcoma and FUS-ERG in acute myeloid leukemia. More than two dozens of transcript variants generated from combinatorial usage of three alternative promoters and multiple alternative splicing events have been reported, but the full-length nature of many of these variants has not been determined. [provided by RefSeq, Apr 2014]

ERG Gene-Disease associations (from GenCC):

• lymphatic malformation 14

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_001136154.1	c.-149-11665T>G		intron_variant	Intron 1 of 11		NP_001129626.1
ERG	NM_001243428.1	c.-149-11665T>G		intron_variant	Intron 1 of 11		NP_001230357.1
ERG	NM_004449.4	c.-149-11665T>G		intron_variant	Intron 1 of 10		NP_004440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000398919.6	c.-149-11665T>G		intron_variant	Intron 1 of 11	1		ENSP00000381891.2
ERG	ENST00000468474.5	n.38-11665T>G		intron_variant	Intron 1 of 7	1
ERG	ENST00000485493.1	n.38-11665T>G		intron_variant	Intron 1 of 4	1

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68781 AN: 151950 Hom.: 15830 Cov.: 33

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.425

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.467

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.453 AC: 68822 AN: 152068 Hom.: 15845 Cov.: 33 AF XY: 0.450 AC XY: 33479 AN XY: 74322

African (AFR) AF: 0.388 AC: 16069 AN: 41456

American (AMR) AF: 0.431 AC: 6593 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1978 AN: 3472

East Asian (EAS) AF: 0.360 AC: 1861 AN: 5172

South Asian (SAS) AF: 0.425 AC: 2051 AN: 4826

European-Finnish (FIN) AF: 0.495 AC: 5241 AN: 10578

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.491 AC: 33373 AN: 67966

Other (OTH) AF: 0.470 AC: 992 AN: 2112

Alfa AF: 0.453 Hom.: 2734

Bravo AF: 0.446

Asia WGS AF: 0.427 AC: 1484 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.58
PhyloP100		-0.067
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2212596; hg19: chr21-39968534;