19-40806356-G-A

Variant names:

• chr19-40806356-G-A
• rs10416308
• NM_080732.4:c.844-199G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_053046.4(EGLN2):​c.844-199G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,074,208 control chromosomes in the GnomAD database, including 18,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5090 hom., cov: 32)
  • Exomes 𝑓: 0.16 (12942 hom.)
• Consequence: EGLN2 NM_053046.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.151
• Publications: 8 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]

ENSG00000268797 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 19-40806356-G-A is Benign according to our data. Variant chr19-40806356-G-A is described in ClinVar as Benign. ClinVar VariationId is 1260751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053046.4. 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.844-199G>A		intron	N/A	NP_542770.2
	EGLN2	NM_053046.4		c.844-199G>A		intron	N/A	NP_444274.1
	RAB4B-EGLN2	NR_037791.1		n.1892-199G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN2	ENST00000303961.9	TSL:1 MANE Select	c.844-199G>A		intron	N/A	ENSP00000307080.3
	EGLN2	ENST00000406058.6	TSL:1	c.844-199G>A		intron	N/A	ENSP00000385253.1
	EGLN2	ENST00000593726.5	TSL:1	c.844-199G>A		intron	N/A	ENSP00000469686.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34253 AN: 151864 Hom.: 5071 Cov.: 32

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.0895

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.210

GnomAD4 exome AF: 0.160 AC: 147707 AN: 922224 Hom.: 12942 Cov.: 12 AF XY: 0.160 AC XY: 72989 AN XY: 456328

African (AFR) AF: 0.431 AC: 9103 AN: 21126

American (AMR) AF: 0.187 AC: 3536 AN: 18902

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 2242 AN: 15996

East Asian (EAS) AF: 0.129 AC: 4065 AN: 31476

South Asian (SAS) AF: 0.172 AC: 9339 AN: 54310

European-Finnish (FIN) AF: 0.144 AC: 4180 AN: 29100

Middle Eastern (MID) AF: 0.153 AC: 430 AN: 2802

European-Non Finnish (NFE) AF: 0.153 AC: 108075 AN: 707860

Other (OTH) AF: 0.166 AC: 6737 AN: 40652

GnomAD4 genome AF: 0.226 AC: 34315 AN: 151984 Hom.: 5090 Cov.: 32 AF XY: 0.222 AC XY: 16490 AN XY: 74308

African (AFR) AF: 0.423 AC: 17486 AN: 41384

American (AMR) AF: 0.188 AC: 2864 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 481 AN: 3472

East Asian (EAS) AF: 0.0895 AC: 463 AN: 5172

South Asian (SAS) AF: 0.173 AC: 833 AN: 4822

European-Finnish (FIN) AF: 0.138 AC: 1455 AN: 10578

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10213 AN: 67964

Other (OTH) AF: 0.208 AC: 439 AN: 2114

Alfa AF: 0.216 Hom.: 546

Bravo AF: 0.237

Asia WGS AF: 0.142 AC: 496 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.8
DANN	Benign	0.84
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs10416308; hg19: chr19-41312261; COSMIC: COSV107337196; COSMIC: COSV107337196;