19-40800316-CTTT-C

Variant names:

• chr19-40800316-CTTT-C
• rs35057638
• ENST00000593726.5:c.-248_-246delTTT

Variant summary

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

The ENST00000593726.5(EGLN2):​c.-248_-246delTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 251,022 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: EGLN2 ENST00000593726.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000593726.5. 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.-234-14_-234-12delTTT		intron	N/A	NP_542770.2	Q96KS0-1
	EGLN2	NM_053046.4		c.-234-14_-234-12delTTT		intron	N/A	NP_444274.1	Q96KS0-1
	RAB4B-EGLN2	NR_037791.1		n.815-14_815-12delTTT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN2	ENST00000593726.5	TSL:1	c.-248_-246delTTT		5_prime_UTR	Exon 1 of 5	ENSP00000469686.1	Q96KS0-1
	EGLN2	ENST00000303961.9	TSL:1 MANE Select	c.-234-14_-234-12delTTT		intron	N/A	ENSP00000307080.3	Q96KS0-1
	EGLN2	ENST00000406058.6	TSL:1	c.-234-14_-234-12delTTT		intron	N/A	ENSP00000385253.1	Q96KS0-1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.0000159 AC: 4 AN: 251022 Hom.: 0 AF XY: 0.0000309 AC XY: 4 AN XY: 129578

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 8242

American (AMR) AF: 0.00 AC: 0 AN: 10040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8208

East Asian (EAS) AF: 0.00 AC: 0 AN: 19644

South Asian (SAS) AF: 0.0000598 AC: 1 AN: 16732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1132

European-Non Finnish (NFE) AF: 0.0000193 AC: 3 AN: 155320

Other (OTH) AF: 0.00 AC: 0 AN: 15134

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35057638; hg19: chr19-41306221;