rs587784024
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_133433.4(NIPBL):c.6893G>A(p.Arg2298His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging 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. R2298C) has been classified as Pathogenic.
Frequency
Consequence
NM_133433.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NIPBL | NM_133433.4 | c.6893G>A | p.Arg2298His | missense_variant | 40/47 | ENST00000282516.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NIPBL | ENST00000282516.13 | c.6893G>A | p.Arg2298His | missense_variant | 40/47 | 1 | NM_133433.4 | P1 | |
NIPBL | ENST00000448238.2 | c.6893G>A | p.Arg2298His | missense_variant | 40/46 | 1 | |||
NIPBL | ENST00000652901.1 | c.6893G>A | p.Arg2298His | missense_variant | 40/46 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cornelia de Lange syndrome 1 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2298 of the NIPBL protein (p.Arg2298His). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg2298 amino acid residue in NIPBL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16236812). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 NIPBL protein function. ClinVar contains an entry for this variant (Variation ID: 159211). This missense change has been observed in individual(s) with Cornelia de Lange syndrome (PMID: 15318302). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Oct 07, 2022 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jan 24, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 12, 2021 | Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15318302, 17640042, 16606884, 16100726, 26725122) - |
NIPBL-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 13, 2023 | The NIPBL c.6893G>A variant is predicted to result in the amino acid substitution p.Arg2298His. This variant has been previously reported as de novo in two individuals with Cornelia de Lange syndrome (Gillis et al. 2004. PubMed ID: 15318302). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Different amino acids substitutions at the same residue (p.Arg2298Cys, p.Arg2298Ser, and p.Arg2298Leu) have also been reported in individuals with Cornelia de Lange syndrome (Gillis et al. 2004. PubMed ID: 15318302; Bhuiyan et al. 2006. PubMed ID: 16236812; Selicorni et al. 2007. PubMed ID: 17661813; Table 4 - Jiao et al. 2019. PubMed ID: 30945278). In summary, c.6893G>A (p.Arg2298His) variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at