chr1-119937416-C-T
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_024408.4(NOTCH2):c.3388G>A(p.Gly1130Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,956 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 Uncertain significance (★★).
Frequency
Consequence
NM_024408.4 missense
Scores
Clinical Significance
Conservation
Publications
- acroosteolysis dominant typeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
- Alagille syndrome due to a NOTCH2 point mutationInheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- Alagille syndromeInheritance: AD Classification: MODERATE Submitted by: Illumina
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000358 AC: 9AN: 251128 AF XY: 0.0000368 show subpopulations
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461740Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727176 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:2
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Hajdu-Cheney syndrome Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1130 of the NOTCH2 protein (p.Gly1130Ser). This variant is present in population databases (rs782078365, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with NOTCH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 134966). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt NOTCH2 protein function with a negative predictive value of 80%. 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. -
Hajdu-Cheney syndrome;C1857761:Alagille syndrome due to a NOTCH2 point mutation Uncertain:1
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not specified Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at