rs373527990
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_024408.4(NOTCH2):c.6956C>T(p.Ala2319Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000491 in 1,608,192 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A2319A) has been classified as Likely benign.
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.6956C>T | p.Ala2319Val | missense_variant | 34/34 | ENST00000256646.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH2 | ENST00000256646.7 | c.6956C>T | p.Ala2319Val | missense_variant | 34/34 | 1 | NM_024408.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000525 AC: 13AN: 247500Hom.: 0 AF XY: 0.0000673 AC XY: 9AN XY: 133794
GnomAD4 exome AF: 0.0000495 AC: 72AN: 1455898Hom.: 1 Cov.: 32 AF XY: 0.0000553 AC XY: 40AN XY: 723172
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152294Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74468
ClinVar
Submissions by phenotype
Hajdu-Cheney syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2319 of the NOTCH2 protein (p.Ala2319Val). This variant is present in population databases (rs373527990, gnomAD 0.007%). 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: 196925). 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 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. - |
NOTCH2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 15, 2022 | The NOTCH2 c.6956C>T variant is predicted to result in the amino acid substitution p.Ala2319Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0072% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-120458389-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 21, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at