rs7533978
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1
The NM_024408.4(NOTCH2):c.939C>T(p.Gly313=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 1,614,062 control chromosomes in the GnomAD database, including 323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.025 ( 152 hom., cov: 32)
Exomes 𝑓: 0.0027 ( 171 hom. )
Consequence
NOTCH2
NM_024408.4 synonymous
NM_024408.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.193
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 Benign. Variant got -19 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BP6
?
Variant 1-119969680-G-A is Benign according to our data. Variant chr1-119969680-G-A is described in ClinVar as [Benign]. Clinvar id is 532030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=0.193 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.083 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH2 | NM_024408.4 | c.939C>T | p.Gly313= | synonymous_variant | 6/34 | ENST00000256646.7 | |
NOTCH2 | NM_001200001.2 | c.939C>T | p.Gly313= | synonymous_variant | 6/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH2 | ENST00000256646.7 | c.939C>T | p.Gly313= | synonymous_variant | 6/34 | 1 | NM_024408.4 | P1 | |
NOTCH2 | ENST00000479412.2 | n.1077C>T | non_coding_transcript_exon_variant | 5/14 | 1 | ||||
NOTCH2 | ENST00000640021.1 | c.*63C>T | 3_prime_UTR_variant, NMD_transcript_variant | 3/12 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0246 AC: 3745AN: 152126Hom.: 151 Cov.: 32
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GnomAD3 exomes AF: 0.00635 AC: 1593AN: 250998Hom.: 59 AF XY: 0.00435 AC XY: 590AN XY: 135622
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GnomAD4 exome AF: 0.00271 AC: 3965AN: 1461818Hom.: 171 Cov.: 33 AF XY: 0.00230 AC XY: 1674AN XY: 727214
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GnomAD4 genome ? AF: 0.0246 AC: 3750AN: 152244Hom.: 152 Cov.: 32 AF XY: 0.0240 AC XY: 1783AN XY: 74444
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ClinVar
Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hajdu-Cheney syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2018 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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