19-40800592-C-T

Position:

chr19-40800592-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000303961.9(EGLN2):c.20C>T(p.Pro7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,605,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P7A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

EGLN2
ENST00000303961.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.25

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:):

RAB4B-EGLN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1620087).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EGLN2	NM_080732.4 linkuse as main transcript	c.20C>T	p.Pro7Leu	missense_variant	2/6	ENST00000303961.9	NP_542770.2
RAB4B-EGLN2	NR_037791.1 linkuse as main transcript	n.1068C>T		non_coding_transcript_exon_variant	8/12
EGLN2	NM_053046.4 linkuse as main transcript	c.20C>T	p.Pro7Leu	missense_variant	2/6		NP_444274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGLN2	ENST00000303961.9 linkuse as main transcript	c.20C>T	p.Pro7Leu	missense_variant	2/6	1	NM_080732.4	ENSP00000307080	P1	Q96KS0-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000413

AC:

AN:

242346

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131560

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000918

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1453640

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2023

The p.P7L variant (also known as c.20C>T), located in coding exon 1 of the EGLN2 gene, results from a C to T substitution at nucleotide position 20. The proline at codon 7 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

.;T;T;T;T;.;.;.;.;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.81

T;.;T;.;T;T;T;T;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.16

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

.;N;.;N;N;.;.;.;.;.

MutationTaster

Benign

0.84

D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.61

.;N;.;N;.;.;.;.;.;.

REVEL

Benign

0.10

Sift

Uncertain

0.0010

.;D;.;D;.;.;.;.;.;.

Sift4G

Uncertain

0.028

D;D;D;D;D;D;D;D;D;D

Polyphen

0.98

.;D;.;D;D;.;.;.;.;.

Vest4

0.23, 0.24, 0.18

MutPred

0.13

Gain of stability (P = 0.0258);Gain of stability (P = 0.0258);Gain of stability (P = 0.0258);Gain of stability (P = 0.0258);Gain of stability (P = 0.0258);Gain of stability (P = 0.0258);Gain of stability (P = 0.0258);Gain of stability (P = 0.0258);Gain of stability (P = 0.0258);Gain of stability (P = 0.0258);

MVP

0.63

MPC

0.57

ClinPred

0.54

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.095

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over