19-40800329-C-T

Position:

• chr19-40800329-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000303961.9(EGLN2):​c.-234-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0638 in 468,440 control chromosomes in the GnomAD database, including 1,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (541 hom., cov: 31)
  • Exomes 𝑓: 0.059 (1156 hom.)
• Consequence: EGLN2 ENST00000303961.9 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003486
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.253

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-40800329-C-T is Benign according to our data. Variant chr19-40800329-C-T is described in ClinVar as [Benign]. Clinvar id is 1182618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGLN2	NM_080732.4	c.-234-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000303961.9	NP_542770.2
RAB4B-EGLN2	NR_037791.1	n.815-10C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant
EGLN2	NM_053046.4	c.-234-10C>T		splice_polypyrimidine_tract_variant, intron_variant			NP_444274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGLN2	ENST00000303961.9	c.-234-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_080732.4	ENSP00000307080	P1

Frequencies

GnomAD3 genomes AF: 0.0733 AC: 10973 AN: 149632 Hom.: 537 Cov.: 31

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0336

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.0512

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0591

GnomAD4 exome AF: 0.0593 AC: 18893 AN: 318692 Hom.: 1156 Cov.: 5 AF XY: 0.0571 AC XY: 9336 AN XY: 163368

Gnomad4 AFR exome AF: 0.0989

Gnomad4 AMR exome AF: 0.0229

Gnomad4 ASJ exome AF: 0.0645

Gnomad4 EAS exome AF: 0.239

Gnomad4 SAS exome AF: 0.0281

Gnomad4 FIN exome AF: 0.0863

Gnomad4 NFE exome AF: 0.0377

Gnomad4 OTH exome AF: 0.0578

GnomAD4 genome AF: 0.0733 AC: 10983 AN: 149748 Hom.: 541 Cov.: 31 AF XY: 0.0765 AC XY: 5587 AN XY: 73074

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.0336

Gnomad4 ASJ AF: 0.0620

Gnomad4 EAS AF: 0.261

Gnomad4 SAS AF: 0.0506

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.0451

Gnomad4 OTH AF: 0.0580

Alfa AF: 0.0552 Hom.: 52

Bravo AF: 0.0719

Asia WGS AF: 0.148 AC: 512 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.6
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs2545761; hg19: chr19-41306234;