chr1-119925638-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_024408.4(NOTCH2):​c.4178G>C​(p.Arg1393Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1393C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

NOTCH2
NM_024408.4 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.50
Variant links:
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 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=0.18319789).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOTCH2NM_024408.4 linkuse as main transcriptc.4178G>C p.Arg1393Pro missense_variant 25/34 ENST00000256646.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOTCH2ENST00000256646.7 linkuse as main transcriptc.4178G>C p.Arg1393Pro missense_variant 25/341 NM_024408.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.012
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
18
DANN
Benign
0.97
DEOGEN2
Benign
0.20
T
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.091
FATHMM_MKL
Benign
0.61
D
LIST_S2
Benign
0.41
T
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.18
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.73
N
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
0.14
N
REVEL
Benign
0.20
Sift
Benign
0.32
T
Sift4G
Benign
0.29
T
Polyphen
0.56
P
Vest4
0.44
MutPred
0.38
Gain of glycosylation at R1393 (P = 0.0322);
MVP
0.83
MPC
0.82
ClinPred
0.55
D
GERP RS
3.9
Varity_R
0.12
gMVP
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-120468261; API