rs17216649

Positions:

• chr19-855966-C-A
• chr19-855966-C-G
• chr19-855966-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001972.4(ELANE):​c.606C>A​(p.Ser202=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,613,084 control chromosomes in the GnomAD database, including 23,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S202S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1546 hom., cov: 32)
  • Exomes 𝑓: 0.16 (22367 hom.)
• Consequence: ELANE NM_001972.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.42

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 19-855966-C-A is Benign according to our data. Variant chr19-855966-C-A is described in ClinVar as [Benign]. Clinvar id is 137199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.42 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELANE	NM_001972.4	c.606C>A	p.Ser202=	synonymous_variant	5/5	ENST00000263621.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELANE	ENST00000263621.2	c.606C>A	p.Ser202=	synonymous_variant	5/5	1	NM_001972.4	P1
ELANE	ENST00000590230.5	c.606C>A	p.Ser202=	synonymous_variant	6/6	5		P1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 18008 AN: 152158 Hom.: 1547 Cov.: 32

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0766

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0394

Gnomad FIN AF: 0.252

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.122 AC: 30214 AN: 248642 Hom.: 2621 AF XY: 0.122 AC XY: 16477 AN XY: 135128

Gnomad AFR exome AF: 0.0289

Gnomad AMR exome AF: 0.0551

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0369

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.163 AC: 238797 AN: 1460808 Hom.: 22367 Cov.: 34 AF XY: 0.159 AC XY: 115695 AN XY: 726710

Gnomad4 AFR exome AF: 0.0234

Gnomad4 AMR exome AF: 0.0584

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.0369

Gnomad4 FIN exome AF: 0.252

Gnomad4 NFE exome AF: 0.186

Gnomad4 OTH exome AF: 0.145

GnomAD4 genome AF: 0.118 AC: 18003 AN: 152276 Hom.: 1546 Cov.: 32 AF XY: 0.118 AC XY: 8820 AN XY: 74458

Gnomad4 AFR AF: 0.0296

Gnomad4 AMR AF: 0.0765

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0396

Gnomad4 FIN AF: 0.252

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.110

Alfa AF: 0.126 Hom.: 662

Bravo AF: 0.104

EpiCase AF: 0.166

EpiControl AF: 0.162

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Cyclical neutropenia;C1859966:Neutropenia, severe congenital, 1, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.10
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs17216649; hg19: chr19-855966;