19-40800316-C-CT

Variant names:

• chr19-40800316-C-CT
• rs35057638
• ENST00000593726.5:c.-246dupT

Variant summary

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

The ENST00000593726.5(EGLN2):​c.-246dupT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 390,398 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: 𝑓 0.00017 (0 hom., cov: 21)
  • Exomes 𝑓: 0.035 (0 hom.)
• Consequence: EGLN2 ENST00000593726.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.329
• Publications: 2 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: Variant has high frequency in the MID (0.0362) population. However there is too low homozygotes in high coverage region: (expected more than 46, got 0).

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.-234-12dupT		intron	N/A	NP_542770.2	Q96KS0-1
	EGLN2	NM_053046.4		c.-234-12dupT		intron	N/A	NP_444274.1	Q96KS0-1
	RAB4B-EGLN2	NR_037791.1		n.815-12dupT		intron	N/A

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.000169 AC: 25 AN: 148210 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000616

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000165

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0353 AC: 8540 AN: 242106 Hom.: 0 Cov.: 0 AF XY: 0.0352 AC XY: 4397 AN XY: 124890

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

African (AFR) AF: 0.0116 AC: 94 AN: 8128

American (AMR) AF: 0.0349 AC: 337 AN: 9670

Ashkenazi Jewish (ASJ) AF: 0.0388 AC: 306 AN: 7892

East Asian (EAS) AF: 0.0365 AC: 690 AN: 18896

South Asian (SAS) AF: 0.0304 AC: 497 AN: 16332

European-Finnish (FIN) AF: 0.0342 AC: 550 AN: 16080

Middle Eastern (MID) AF: 0.0443 AC: 48 AN: 1084

European-Non Finnish (NFE) AF: 0.0370 AC: 5530 AN: 149470

Other (OTH) AF: 0.0335 AC: 488 AN: 14554

⚠️ 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 AF: 0.000169 AC: 25 AN: 148292 Hom.: 0 Cov.: 21 AF XY: 0.000138 AC XY: 10 AN XY: 72264

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

African (AFR) AF: 0.0000247 AC: 1 AN: 40472

American (AMR) AF: 0.000268 AC: 4 AN: 14944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.000395 AC: 2 AN: 5068

South Asian (SAS) AF: 0.00 AC: 0 AN: 4686

European-Finnish (FIN) AF: 0.000616 AC: 6 AN: 9742

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.000165 AC: 11 AN: 66756

Other (OTH) AF: 0.00 AC: 0 AN: 2032

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000134882), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000874 Hom.: 69

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.33
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;