19-40799402-G-T

Variant names:

• chr19-40799402-G-T
• rs192477377
• NM_080732.4:c.-235+140G>T

Variant summary

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

The NM_080732.4(EGLN2):​c.-235+140G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0602 in 144,408 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (347 hom., cov: 22)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EGLN2 NM_080732.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0670
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 19-40799402-G-T is Benign according to our data. Variant chr19-40799402-G-T is described in ClinVar as Benign. ClinVar VariationId is 1283406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

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.-235+140G>T		intron	N/A	NP_542770.2	Q96KS0-1
	RAB4B-EGLN2	NR_037791.1		n.815-937G>T		intron	N/A
	EGLN2	NM_053046.4		c.-471G>T		upstream_gene	N/A	NP_444274.1	Q96KS0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN2	ENST00000303961.9	TSL:1 MANE Select	c.-235+140G>T		intron	N/A	ENSP00000307080.3	Q96KS0-1
	RAB4B-EGLN2	ENST00000594136.2	TSL:2	n.*16-937G>T		intron	N/A	ENSP00000469872.1
	EGLN2	ENST00000863135.1		c.-235+140G>T		intron	N/A	ENSP00000533194.1

Frequencies

GnomAD3 genomes AF: 0.0601 AC: 8679 AN: 144296 Hom.: 345 Cov.: 22

Gnomad AFR AF: 0.0816

Gnomad AMI AF: 0.0540

Gnomad AMR AF: 0.0303

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.0405

Gnomad FIN AF: 0.0924

Gnomad MID AF: 0.0642

Gnomad NFE AF: 0.0431

Gnomad OTH AF: 0.0474

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 8

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 12

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0602 AC: 8688 AN: 144408 Hom.: 347 Cov.: 22 AF XY: 0.0622 AC XY: 4383 AN XY: 70486

African (AFR) AF: 0.0818 AC: 3187 AN: 38960

American (AMR) AF: 0.0302 AC: 448 AN: 14824

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 145 AN: 3392

East Asian (EAS) AF: 0.185 AC: 853 AN: 4602

South Asian (SAS) AF: 0.0399 AC: 180 AN: 4514

European-Finnish (FIN) AF: 0.0924 AC: 906 AN: 9800

Middle Eastern (MID) AF: 0.0652 AC: 18 AN: 276

European-Non Finnish (NFE) AF: 0.0431 AC: 2810 AN: 65178

Other (OTH) AF: 0.0473 AC: 96 AN: 2028

Alfa AF: 0.0520 Hom.: 28

Bravo AF: 0.0627

Asia WGS AF: 0.0930 AC: 312 AN: 3342

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	14
DANN	Benign	0.86
PhyloP100		-0.067
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs192477377; hg19: chr19-41305307;