19-40800577-A-G

Variant names:

• chr19-40800577-A-G
• rs1228124095
• NM_080732.4:c.5A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_080732.4(EGLN2):​c.5A>G​(p.Asp2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,444,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: EGLN2 NM_080732.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34259343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGLN2	NM_080732.4	c.5A>G	p.Asp2Gly	missense_variant	Exon 2 of 6	ENST00000303961.9	NP_542770.2
EGLN2	NM_053046.4	c.5A>G	p.Asp2Gly	missense_variant	Exon 2 of 6		NP_444274.1
RAB4B-EGLN2	NR_037791.1	n.1053A>G		non_coding_transcript_exon_variant	Exon 8 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGLN2	ENST00000303961.9	c.5A>G	p.Asp2Gly	missense_variant	Exon 2 of 6	1	NM_080732.4	ENSP00000307080.3
RAB4B-EGLN2	ENST00000594136.2	n.*254A>G		non_coding_transcript_exon_variant	Exon 8 of 12	2		ENSP00000469872.1
RAB4B-EGLN2	ENST00000594136.2	n.*254A>G		3_prime_UTR_variant	Exon 8 of 12	2		ENSP00000469872.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000132 AC: 19 AN: 1444702 Hom.: 0 Cov.: 32 AF XY: 0.0000195 AC XY: 14 AN XY: 716690

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: 0.0000163

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D2G variant (also known as c.5A>G), located in coding exon 1 of the EGLN2 gene, results from an A to G substitution at nucleotide position 5. The aspartic acid at codon 2 is replaced by glycine, 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	0.16
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	.;T;T;T;T;.;.;.;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.78	T;.;T;.;T;T;T;T;T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	.;N;.;N;N;.;.;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.67	.;N;.;N;.;.;.;.;.;.
REVEL	Benign	0.17
Sift	Pathogenic	0.0	.;D;.;D;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;T;D;T;T;D;D;D;D;D
Polyphen		0.99	.;D;.;D;D;.;.;.;.;.
Vest4		0.40, 0.40, 0.25
MutPred		0.17		Gain of glycosylation at P4 (P = 0.0722);Gain of glycosylation at P4 (P = 0.0722);Gain of glycosylation at P4 (P = 0.0722);Gain of glycosylation at P4 (P = 0.0722);Gain of glycosylation at P4 (P = 0.0722);Gain of glycosylation at P4 (P = 0.0722);Gain of glycosylation at P4 (P = 0.0722);Gain of glycosylation at P4 (P = 0.0722);Gain of glycosylation at P4 (P = 0.0722);Gain of glycosylation at P4 (P = 0.0722);
MVP		0.61
MPC		0.74
ClinPred		0.73	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.29
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs1228124095; hg19: chr19-41306482;