rs587784020
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP2PP3_ModeratePP5
The NM_133433.4(NIPBL):c.6646T>C(p.Tyr2216His) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y2216S) has been classified as Pathogenic.
Frequency
Consequence
NM_133433.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NIPBL | NM_133433.4 | c.6646T>C | p.Tyr2216His | missense_variant | 39/47 | ENST00000282516.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NIPBL | ENST00000282516.13 | c.6646T>C | p.Tyr2216His | missense_variant | 39/47 | 1 | NM_133433.4 | P1 | |
NIPBL | ENST00000448238.2 | c.6646T>C | p.Tyr2216His | missense_variant | 39/46 | 1 | |||
NIPBL | ENST00000652901.1 | c.6646T>C | p.Tyr2216His | missense_variant | 39/46 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1438070Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 714922
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cornelia de Lange syndrome 1 Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 13, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 04, 2018 | This sequence change replaces tyrosine with histidine at codon 2216 of the NIPBL protein (p.Tyr2216His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Cornelia de Lange syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 159205). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Two other missense variants at this residue (p.Tyr2216Cys and p.Try2216Ser) in NIPBL have been determined to be clinically significant (PMID:24874887, 24635725). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at