chr1-119915829-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_024408.4(NOTCH2):c.6893G>A(p.Arg2298Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000321 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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.6893G>A | p.Arg2298Gln | missense_variant | 34/34 | ENST00000256646.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH2 | ENST00000256646.7 | c.6893G>A | p.Arg2298Gln | missense_variant | 34/34 | 1 | NM_024408.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152166Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000124 AC: 31AN: 250868Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 135636
GnomAD4 exome AF: 0.000339 AC: 495AN: 1461750Hom.: 0 Cov.: 32 AF XY: 0.000369 AC XY: 268AN XY: 727174
GnomAD4 genome AF: 0.000151 AC: 23AN: 152284Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74460
ClinVar
Submissions by phenotype
NOTCH2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 03, 2023 | The NOTCH2 c.6893G>A variant is predicted to result in the amino acid substitution p.Arg2298Gln. To our knowledge, this variant has not been reported in the literature. Of note, a different substitution at the same codon (p.Arg2298Trp) has been reported in an individual with congenital anomalies of the kidney and urinary tract (CAKUT), but the significance is unknown (van der Ven et al. 2018. PubMed ID: 30143558). This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-120458452-C-T). In ClinVar, this variant is interpreted as uncertain/likely benign (https://preview.ncbi.nlm.nih.gov/clinvar/variation/291198/). This variant could be benign. 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) | Dec 13, 2017 | - - |
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 | Oct 31, 2018 | - - |
Hajdu-Cheney syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at