1-119915347-T-C

Position:

• chr1-119915347-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_024408.4(NOTCH2):​c.7375A>G​(p.Met2459Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2459I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOTCH2 NM_024408.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NOTCH2. . Gene score misZ 3.5024 (greater than the threshold 3.09). Trascript score misZ 6.0283 (greater than threshold 3.09). GenCC has associacion of gene with Alagille syndrome due to a NOTCH2 point mutation, Alagille syndrome, Acroosteolysis dominant type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08246356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.7375A>G	p.Met2459Val	missense_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.7375A>G	p.Met2459Val	missense_variant	34/34	1	NM_024408.4	ENSP00000256646.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Mar 07, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.11	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.17
Sift	Benign	0.24	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.15		Loss of glycosylation at P2462 (P = 0.1187);
MVP		0.58
MPC		0.16
ClinPred		0.094	T
GERP RS		4.8
Varity_R		0.066
gMVP		0.43

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: rs1649025876; hg19: chr1-120457970;