chr19-852167-C-T

Variant names:

• chr19-852167-C-T
• rs556325692
• ENST00000590230.5:c.-120-42C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000958526.1(ELANE):​c.-120-42C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 763,138 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (2 hom.)
• Consequence: ELANE ENST00000958526.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.578
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-852167-C-T is Benign according to our data. Variant chr19-852167-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 678420.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00225 (343/152366) while in subpopulation NFE AF = 0.00138 (94/68038). AF 95% confidence interval is 0.00115. There are 5 homozygotes in GnomAd4. There are 226 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 343 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.-162C>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.-120-42C>T		intron	N/A	ENSP00000466090.1	P08246
	ELANE	ENST00000958526.1		c.-120-42C>T		intron	N/A	ENSP00000628585.1
	ELANE	ENST00000263621.2	TSL:1 MANE Select	c.-162C>T		upstream_gene	N/A	ENSP00000263621.1	P08246

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 343 AN: 152248 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00176 AC: 1072 AN: 610772 Hom.: 2 Cov.: 8 AF XY: 0.00173 AC XY: 544 AN XY: 315104

African (AFR) AF: 0.000127 AC: 2 AN: 15802

American (AMR) AF: 0.00103 AC: 24 AN: 23222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15774

East Asian (EAS) AF: 0.00 AC: 0 AN: 31752

South Asian (SAS) AF: 0.0000384 AC: 2 AN: 52060

European-Finnish (FIN) AF: 0.0151 AC: 456 AN: 30292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2374

European-Non Finnish (NFE) AF: 0.00132 AC: 539 AN: 408004

Other (OTH) AF: 0.00156 AC: 49 AN: 31492

GnomAD4 genome AF: 0.00225 AC: 343 AN: 152366 Hom.: 5 Cov.: 32 AF XY: 0.00303 AC XY: 226 AN XY: 74508

African (AFR) AF: 0.000192 AC: 8 AN: 41596

American (AMR) AF: 0.000915 AC: 14 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0213 AC: 226 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00138 AC: 94 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.000744

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.3
DANN	Benign	0.60
PhyloP100		0.58
PromoterAI		0.0025	Neutral
Mutation Taster		=100/0	polymorphism

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: rs556325692; hg19: chr19-852167;