19-40800582-C-T

Variant names:

• chr19-40800582-C-T
• rs760499657
• NM_080732.4:c.10C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080732.4(EGLN2):​c.10C>T​(p.Pro4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. P4L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EGLN2 NM_080732.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85
• Publications: 0 publications found

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

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.098156095).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080732.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN2	NM_080732.4	MANE Select	c.10C>T	p.Pro4Ser	missense	Exon 2 of 6	NP_542770.2	Q96KS0-1
	EGLN2	NM_053046.4		c.10C>T	p.Pro4Ser	missense	Exon 2 of 6	NP_444274.1	Q96KS0-1
	RAB4B-EGLN2	NR_037791.1		n.1058C>T		non_coding_transcript_exon	Exon 8 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN2	ENST00000303961.9	TSL:1 MANE Select	c.10C>T	p.Pro4Ser	missense	Exon 2 of 6	ENSP00000307080.3	Q96KS0-1
	EGLN2	ENST00000406058.6	TSL:1	c.10C>T	p.Pro4Ser	missense	Exon 2 of 6	ENSP00000385253.1	Q96KS0-1
	EGLN2	ENST00000593726.5	TSL:1	c.10C>T	p.Pro4Ser	missense	Exon 1 of 5	ENSP00000469686.1	Q96KS0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000848 AC: 2 AN: 235738 AF XY: 0.0000156

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448592 Hom.: 0 Cov.: 32 AF XY: 0.00000417 AC XY: 3 AN XY: 719250

African (AFR) AF: 0.00 AC: 0 AN: 33286

American (AMR) AF: 0.00 AC: 0 AN: 43944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25504

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39364

South Asian (SAS) AF: 0.00 AC: 0 AN: 84980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5178

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105236

Other (OTH) AF: 0.00 AC: 0 AN: 59678

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.077
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.9
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.035
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.42	B
Vest4		0.39
MutPred		0.15		Loss of catalytic residue at P4 (P = 8e-04)
MVP		0.36
MPC		0.57
ClinPred		0.36	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.082
gMVP		0.29
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs760499657; hg19: chr19-41306487;