chr19-852990-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_001972.4(ELANE):c.182C>T(p.Ala61Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A61E) has been classified as Uncertain significance.
Frequency
Consequence
NM_001972.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ELANE | NM_001972.4 | c.182C>T | p.Ala61Val | missense_variant | 2/5 | ENST00000263621.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ELANE | ENST00000263621.2 | c.182C>T | p.Ala61Val | missense_variant | 2/5 | 1 | NM_001972.4 | P1 | |
ELANE | ENST00000590230.5 | c.182C>T | p.Ala61Val | missense_variant | 3/6 | 5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 7.01e-7 AC: 1AN: 1427446Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 709058
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cyclical neutropenia;C1859966:Neutropenia, severe congenital, 1, autosomal dominant Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 20, 2023 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ELANE protein function. ClinVar contains an entry for this variant (Variation ID: 16740). This variant is also known as p.Ala32Val. This missense change has been observed in individual(s) with congenital neutropenia and/or cyclic neutropenia (PMID: 10581030, 11675333, 19036076, 23463630, 25703294). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 61 of the ELANE protein (p.Ala61Val). - |
Cyclical neutropenia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1999 | - - |
Autoinflammatory syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 01, 2018 | - - |
Neutropenia, severe congenital, 1, autosomal dominant Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital | Oct 23, 2023 | This heterozygous mis-sense variant is identified in a 2.6 years girl with recurrent mucosal infection, oral candidiasis, cervical adenopathy, and severe neutropenia with ANC 230, suggestive of congenital neutropenia. This nucleotide change is absent in gnomAD database [PM2]. Insilico prediction [REVEL: 0.5] predicts uncertain nature of this variant. A clinvar entry for this variant is available. This variant is submitted to clinvar database [Variation ID: 16740] with “Pathogenic” interpretation by multiple submitter [PP5]. 9 pathogenic or likely pathogenic reported variants are found surrounding this region in exon 2 without any mis-sense benign change, considering this as a hotspot region [PM1]. PMID [23463630] Based on the clinical correlation and available evidence, this variant is classified as "Likely Pathogenic" - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at