rs1553193574

Positions:

• chr1-119916271-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_024408.4(NOTCH2):​c.6449_6450delCT​(p.Pro2150fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOTCH2 NM_024408.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

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 exon, not predicted to undergo nonsense mediated mRNA decay. There are 30 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-119916271-CAG-C is Pathogenic according to our data. Variant chr1-119916271-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 463176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-119916271-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.6449_6450delCT	p.Pro2150fs	frameshift_variant	34/34	ENST00000256646.7	NP_077719.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.6449_6450delCT	p.Pro2150fs	frameshift_variant	34/34	1	NM_024408.4	ENSP00000256646.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hajdu-Cheney syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 13, 2017

For these reasons, this variant has been classified as Pathogenic. Multiple truncating variants in the last exon of NOTCH2 have been reported in individuals with HCS resulting in deletion of the PEST (proline(P), glutamic acid(E), serine(S), threonine(T)) domain at the C-terminus which regulates the Notch intracellular domain (NICD) with ankyrin repeats (PMID: 21378989, 21378985, 8755249). Specifically, PEST domains are implicated in mediating proteosomal degradation of proteins with ankyrin-repeat domains, and loss of this PEST domain is expected to result in a stable, functional but constitutively active NICD in the NOTCH2 protein (PMID: 21378989, 8755249). This variant has been reported in several individuals with Hajdu-Cheney syndrome (HCS) (PMID: 21378985, 21378989). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the NOTCH2 (p.Pro2150Argfs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 322 amino acids of the NOTCH2 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553193574; hg19: chr1-120458894; COSMIC: COSV105067607;