rs17216663

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001972.4(ELANE):c.770C>T(p.Pro257Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00743 in 1,613,032 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0059 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0076 ( 57 hom. )

Consequence

ELANE
NM_001972.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.526

Publications

15 publications found

Variant links:

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

ELANE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 53 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.71822 (below the threshold of 3.09). Trascript score misZ: -0.55649 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant severe congenital neutropenia, cyclic hematopoiesis, neutropenia.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060737133).

BP6

Variant 19-856130-C-T is Benign according to our data. Variant chr19-856130-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00587 (894/152358) while in subpopulation NFE AF = 0.00907 (617/68024). AF 95% confidence interval is 0.00848. There are 6 homozygotes in GnomAd4. There are 413 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 894 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELANE	NM_001972.4 link	c.770C>T	p.Pro257Leu	missense_variant	Exon 5 of 5	ENST00000263621.2	NP_001963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELANE	ENST00000263621.2 link	c.770C>T	p.Pro257Leu	missense_variant	Exon 5 of 5	1	NM_001972.4	ENSP00000263621.1
ELANE	ENST00000590230.5 link	c.770C>T	p.Pro257Leu	missense_variant	Exon 6 of 6	5		ENSP00000466090.1

Frequencies

GnomAD3 genomes

AF:

0.00587

AC:

893

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00877

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00641

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00907

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.00640

AC:

1596

AN:

249410

AF XY:

0.00670

show subpopulations

Gnomad AFR exome

AF:

0.000626

Gnomad AMR exome

AF:

0.00764

Gnomad ASJ exome

AF:

0.0131

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00855

Gnomad OTH exome

AF:

0.00886

GnomAD4 exome

AF:

0.00759

AC:

11091

AN:

1460674

Hom.:

Cov.:

AF XY:

0.00766

AC XY:

5563

AN XY:

726600

show subpopulations

African (AFR)

AF:

0.00170

AC:

AN:

33480

American (AMR)

AF:

0.00825

AC:

369

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

331

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00556

AC:

480

AN:

86258

European-Finnish (FIN)

AF:

0.00119

AC:

AN:

52224

Middle Eastern (MID)

AF:

0.0107

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00835

AC:

9287

AN:

1112004

Other (OTH)

AF:

0.00734

AC:

443

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

750

1500

2250

3000

3750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

334

668

1002

1336

1670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00587

AC:

894

AN:

152358

Hom.:

Cov.:

AF XY:

0.00554

AC XY:

413

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00127

AC:

AN:

41596

American (AMR)

AF:

0.00882

AC:

135

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00642

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00907

AC:

617

AN:

68024

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00794

Hom.:

Bravo

AF:

0.00631

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0108

AC:

ExAC

AF:

0.00591

AC:

717

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0115

EpiControl

AF:

0.0132

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23454784, 11675333, 22995991, 27153395, 18043239) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ELANE: BP4, BS2 -

not specified

Benign:2

Dec 01, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Benign:1

Mar 14, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.33

T;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.38

.;T

MetaRNN

Benign

0.0061

T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.4

L;L

PhyloP100

0.53

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.97

.;N

REVEL

Benign

0.12

Sift

Uncertain

0.0080

.;D

Sift4G

Benign

0.20

T;T

Polyphen

0.010

B;B

Vest4

0.19

MVP

0.63

MPC

0.56

ClinPred

0.022

GERP RS

1.2

Varity_R

0.058

gMVP

0.54

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over