dbSNP rs892202419: EGLN2:p.Ser3Arg (chr19-40800581-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_080732.4(EGLN2):c.9C>A(p.Ser3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,092 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S3G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EGLN2
NM_080732.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.514

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 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=0.13495964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGLN2	NM_080732.4 link	c.9C>A	p.Ser3Arg	missense_variant	Exon 2 of 6	ENST00000303961.9	NP_542770.2	Q96KS0-1A0A024R0R2
EGLN2	NM_053046.4 link	c.9C>A	p.Ser3Arg	missense_variant	Exon 2 of 6		NP_444274.1	Q96KS0-1A0A024R0R2
RAB4B-EGLN2	NR_037791.1 link	n.1057C>A		non_coding_transcript_exon_variant	Exon 8 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EGLN2	ENST00000303961.9 link	c.9C>A	p.Ser3Arg	missense_variant	Exon 2 of 6	1	NM_080732.4	ENSP00000307080.3	Q96KS0-1
RAB4B-EGLN2	ENST00000594136.2 link	n.*258C>A		non_coding_transcript_exon_variant	Exon 8 of 12	2		ENSP00000469872.1
RAB4B-EGLN2	ENST00000594136.2 link	n.*258C>A		3_prime_UTR_variant	Exon 8 of 12	2		ENSP00000469872.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447092

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718378

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:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

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

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.097

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.77

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

M_CAP

Benign

0.015

MetaRNN

Benign

0.13

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

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

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.11

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

REVEL

Benign

0.15

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

D;T;D;T;T;D;D;D;D;D

Polyphen

0.11

.;B;.;B;B;.;.;.;.;.

Vest4

0.20, 0.21, 0.17

MutPred

0.17

Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);

MVP

0.55

MPC

0.63

ClinPred

0.60

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.18

gMVP

0.47

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over