chr19-852234-C-T

Variant names:

• chr19-852234-C-T
• rs17216607
• ENST00000590230.5:c.-95C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000958526.1(ELANE):​c.-95C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000851 in 1,458,564 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00044 (1 hom.)
• Consequence: ELANE ENST00000958526.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0280
• Publications: 1 publications found

Genes affected

ELANE (HGNC:3309): (elastase, neutrophil expressed) Elastases form a subfamily of serine proteases that hydrolyze many proteins in addition to elastin. Humans have six elastase genes which encode structurally similar proteins. The encoded preproprotein is proteolytically processed to generate the active protease. Following activation, this protease hydrolyzes proteins within specialized neutrophil lysosomes, called azurophil granules, as well as proteins of the extracellular matrix. The enzyme may play a role in degenerative and inflammatory diseases through proteolysis of collagen-IV and elastin. This protein also degrades the outer membrane protein A (OmpA) of E. coli as well as the virulence factors of such bacteria as Shigella, Salmonella and Yersinia. Mutations in this gene are associated with cyclic neutropenia and severe congenital neutropenia (SCN). This gene is present in a gene cluster on chromosome 19. [provided by RefSeq, Jan 2016]

ELANE Gene-Disease associations (from GenCC):

• neutropenia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• cyclic hematopoiesis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant severe congenital neutropenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-852234-C-T is Benign according to our data. Variant chr19-852234-C-T is described in ClinVar as Benign. ClinVar VariationId is 1241499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00441 (672/152226) while in subpopulation AFR AF = 0.0148 (616/41550). AF 95% confidence interval is 0.0139. There are 3 homozygotes in GnomAd4. There are 324 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 672 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000958526.1. 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
	ELANE	NM_001972.4	MANE Select	c.-95C>T		upstream_gene	N/A	NP_001963.1	P08246

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELANE	ENST00000590230.5	TSL:5	c.-95C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	ENSP00000466090.1	P08246
	ELANE	ENST00000958526.1		c.-95C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	ENSP00000628585.1
	ELANE	ENST00000590230.5	TSL:5	c.-95C>T		5_prime_UTR	Exon 2 of 6	ENSP00000466090.1	P08246

Frequencies

GnomAD3 genomes AF: 0.00440 AC: 670 AN: 152108 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.000436 AC: 569 AN: 1306338 Hom.: 1 Cov.: 21 AF XY: 0.000357 AC XY: 232 AN XY: 649302

African (AFR) AF: 0.0149 AC: 449 AN: 30140

American (AMR) AF: 0.00109 AC: 40 AN: 36658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24492

East Asian (EAS) AF: 0.00 AC: 0 AN: 35822

South Asian (SAS) AF: 0.0000506 AC: 4 AN: 79098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34642

Middle Eastern (MID) AF: 0.000726 AC: 3 AN: 4134

European-Non Finnish (NFE) AF: 0.0000199 AC: 20 AN: 1006284

Other (OTH) AF: 0.000962 AC: 53 AN: 55068

GnomAD4 genome AF: 0.00441 AC: 672 AN: 152226 Hom.: 3 Cov.: 31 AF XY: 0.00435 AC XY: 324 AN XY: 74412

African (AFR) AF: 0.0148 AC: 616 AN: 41550

American (AMR) AF: 0.00288 AC: 44 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68010

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.000628 Hom.: 0

Bravo AF: 0.00492

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

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	-0.88
CADD	Benign	8.1
DANN	Benign	0.77
PhyloP100		0.028
PromoterAI		0.041	Neutral
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs17216607; hg19: chr19-852234;