Genetic Variant ENST00000593726.5:c.-247_-246delTT (chr19-40800316-CTT-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The ENST00000593726.5(EGLN2):c.-247_-246delTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000548 in 397,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 21)

Exomes 𝑓: 0.00087 ( 0 hom. )

Consequence

EGLN2
ENST00000593726.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.329

Publications

2 publications found

Variant links:

Genes affected

EGLN2 (HGNC:14660): (egl-9 family hypoxia inducible factor 2) The hypoxia inducible factor (HIF) is a transcriptional complex that is involved in oxygen homeostasis. At normal oxygen levels, the alpha subunit of HIF is targeted for degration by prolyl hydroxylation. This gene encodes an enzyme responsible for this post-translational modification. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the upstream RAB4B (RAB4B, member RAS oncogene family) gene. [provided by RefSeq, Feb 2011]

EGLN2 links:

RAB4B-EGLN2 (HGNC:44465): (RAB4B-EGLN2 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring RAB4B (RAB4B, member RAS oncogene family) and EGLN2 (egl nine homolog 2) genes on chromosome 19. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

RAB4B-EGLN2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000593726.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EGLN2	NM_080732.4	MANE Select	c.-234-13_-234-12delTT	intron	N/A	NP_542770.2	Q96KS0-1
EGLN2	NM_053046.4		c.-234-13_-234-12delTT	intron	N/A	NP_444274.1	Q96KS0-1
RAB4B-EGLN2	NR_037791.1		n.815-13_815-12delTT	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EGLN2	ENST00000593726.5	TSL:1	c.-247_-246delTT	5_prime_UTR	Exon 1 of 5	ENSP00000469686.1	Q96KS0-1
EGLN2	ENST00000303961.9	TSL:1 MANE Select	c.-234-13_-234-12delTT	intron	N/A	ENSP00000307080.3	Q96KS0-1
EGLN2	ENST00000406058.6	TSL:1	c.-234-13_-234-12delTT	intron	N/A	ENSP00000385253.1	Q96KS0-1

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

148226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000495

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000866

AC:

216

AN:

249446

Hom.:

AF XY:

0.000909

AC XY:

117

AN XY:

128728

show subpopulations

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

African (AFR)

AF:

0.00195

AC:

AN:

8188

American (AMR)

AF:

0.00100

AC:

AN:

9952

Ashkenazi Jewish (ASJ)

AF:

0.000613

AC:

AN:

8158

East Asian (EAS)

AF:

0.000767

AC:

AN:

19550

South Asian (SAS)

AF:

0.000842

AC:

AN:

16630

European-Finnish (FIN)

AF:

0.00103

AC:

AN:

16498

Middle Eastern (MID)

AF:

0.000891

AC:

AN:

1122

European-Non Finnish (NFE)

AF:

0.000830

AC:

128

AN:

154302

Other (OTH)

AF:

0.000665

AC:

AN:

15046

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000135

AC:

AN:

148226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72176

show subpopulations

African (AFR)

AF:

0.0000495

AC:

AN:

40366

American (AMR)

AF:

0.00

AC:

AN:

14926

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3418

East Asian (EAS)

AF:

0.00

AC:

AN:

5082

South Asian (SAS)

AF:

0.00

AC:

AN:

4700

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9738

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66782

Other (OTH)

AF:

0.00

AC:

AN:

2010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.33

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over