rs587609362
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_024408.4(NOTCH2):c.3995G>A(p.Arg1332His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000493 in 1,601,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1332C) has been classified as Uncertain significance.
Frequency
Consequence
NM_024408.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH2 | NM_024408.4 | c.3995G>A | p.Arg1332His | missense_variant | 24/34 | ENST00000256646.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH2 | ENST00000256646.7 | c.3995G>A | p.Arg1332His | missense_variant | 24/34 | 1 | NM_024408.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000429 AC: 10AN: 233044Hom.: 0 AF XY: 0.0000479 AC XY: 6AN XY: 125172
GnomAD4 exome AF: 0.0000449 AC: 65AN: 1448912Hom.: 0 Cov.: 31 AF XY: 0.0000445 AC XY: 32AN XY: 719236
GnomAD4 genome ? AF: 0.0000919 AC: 14AN: 152270Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74446
ClinVar
Submissions by phenotype
Hajdu-Cheney syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1332 of the NOTCH2 protein (p.Arg1332His). This variant is present in population databases (rs587609362, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of Alagille syndrome (PMID: 28776642). ClinVar contains an entry for this variant (Variation ID: 134973). 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 not expected to disrupt NOTCH2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
NOTCH2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 04, 2023 | The NOTCH2 c.3995G>A variant is predicted to result in the amino acid substitution p.Arg1332His. This variant has been reported in the heterozygous state in an infant with neonatal cholestasis, but no other features of Allagille syndrome (Stalke et al. 2018. PubMed ID: 28776642). This variant is reported in 0.030% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-120469132-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hajdu-Cheney syndrome;C1857761:Alagille syndrome due to a NOTCH2 point mutation Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 14, 2022 | - - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at