rs312262801
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_024408.4(NOTCH2):c.6007C>T(p.Arg2003*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,126 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R2003R) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
NOTCH2
NM_024408.4 stop_gained
NM_024408.4 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 0.611
Genes affected
NOTCH2 (HGNC:7882): (notch receptor 2) This gene encodes a member of the Notch family. Members of this Type 1 transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway which regulates interactions between physically adjacent cells. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signaling pathway that plays a key role in development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remain to be determined. This protein is cleaved in the trans-Golgi network, and presented on the cell surface as a heterodimer. This protein functions as a receptor for membrane bound ligands, and may play a role in vascular, renal and hepatic development. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 40 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-119917685-G-A is Pathogenic according to our data. Variant chr1-119917685-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 41266.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-119917685-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NOTCH2 | NM_024408.4 | c.6007C>T | p.Arg2003* | stop_gained | 33/34 | ENST00000256646.7 | NP_077719.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NOTCH2 | ENST00000256646.7 | c.6007C>T | p.Arg2003* | stop_gained | 33/34 | 1 | NM_024408.4 | ENSP00000256646.2 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32
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GnomAD4 genome 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74302
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 15, 2024 | The c.6007C>T (p.R2003*) alteration, located in exon 33 (coding exon 33) of the NOTCH2 gene, consists of a C to T substitution at nucleotide position 6007. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 2003. This alteration occurs at the 3' terminus of the NOTCH2 gene and is not expected to trigger nonsense-mediated mRNA decay. for NOTCH2-related Alagille syndrome; however, its clinical significance for Hajdu-Cheney syndrome is uncertain This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in one individual and heterozygous in multiple individuals with liver pruritis, cholestasis, cardiac anomalies, butterfly-like vertebrae, typical facial features, small for gestational age, and/or other clinical features consistent with Alagille syndrome (Kamath, 2012; Lin, 2012; Alfares, 2017; Li, 2022; Ferrandino, 2024). In an assay testing NOTCH2 function, this variant showed a functionally abnormal result (Kamath, 2012). Based on the available evidence, this alteration is classified as likely pathogenic. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 23, 2017 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at