rs1283460236
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_024408.4(NOTCH2):āc.6079A>Gā(p.Lys2027Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
NOTCH2
NM_024408.4 missense
NM_024408.4 missense
Scores
1
11
7
Clinical Significance
Conservation
PhyloP100: 3.33
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 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, NOTCH2
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH2 | NM_024408.4 | c.6079A>G | p.Lys2027Glu | missense_variant | 34/34 | ENST00000256646.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH2 | ENST00000256646.7 | c.6079A>G | p.Lys2027Glu | missense_variant | 34/34 | 1 | NM_024408.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727246
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74342
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 19, 2014 | The c.6079A>G (p.K2027E) alteration is located in exon 34 (coding exon 34) of the NOTCH2 gene. This alteration results from a A to G substitution at nucleotide position 6079, causing the lysine (K) at amino acid position 2027 to be replaced by a glutamic acid (E). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the NOTCH2 c.6079A>G alteration was not observed among 6,497 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The altered nucleotide is conserved throughout evolution:_x000D_ The c.6079A nucleotide is well conserved in available vertebrate species, except the blowfish, stickleback, and the zebrafish._x000D_ _x000D_ The altered amino acid is conserved throughout evolution:_x000D_ The p.K2027 amino acid is completely conserved in available mammal species. The c.6079A>G (p.K2027E) alteration is located in coding exon 34 of the NOTCH2 gene. The alteration results from an A to G substitution at nucleotide position 6079, causing the Lysine (K) at amino acid position 2027 to be replaced by a Glutamic acid (E). The amino acid is located in a functionally important protein domain:_x000D_ The p.K2027E amino acid is located in the ankyrin repeat domain of the NOTCH2 protein. The ankyrin repeat domain is located in the intracellular part of the NOTCH2 protein and mediates protein-protein interactions. Pathogenic alterations in the ankyrin repeat domain are associated with Alagille syndrome and are predicted to affect the ability of the Notch intracellular domain to bind to other transcription factors (Penton, 2012). In silico prediction is conflicting:_x000D_ The p.K2027E alteration is predicted to be benign by Polyphen and deleterious by SIFT in silico analyses._x000D_ The alteration is predicted not to affect splicing by in silico models:_x000D_ Based on BDGP and ESEfinder splice site in silico tools, this alteration does not have any significant effect on the native acceptor/donor splice site; however, direct evidence is unavailable Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
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 02, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Uncertain
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Loss of ubiquitination at K2027 (P = 0.0283);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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