rs115325955
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_024408.4(NOTCH2):c.3519C>T(p.Cys1173=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000967 in 1,613,110 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00081 ( 11 hom. )
Consequence
NOTCH2
NM_024408.4 synonymous
NM_024408.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.123
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=-0.42).
BP6
?
Variant 1-119937285-G-A is Benign according to our data. Variant chr1-119937285-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 286618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=-0.123 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00243 (370/152304) while in subpopulation AFR AF= 0.00606 (252/41560). AF 95% confidence interval is 0.00545. There are 0 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 370 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH2 | NM_024408.4 | c.3519C>T | p.Cys1173= | synonymous_variant | 21/34 | ENST00000256646.7 | |
NOTCH2 | NM_001200001.2 | c.3519C>T | p.Cys1173= | synonymous_variant | 21/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH2 | ENST00000256646.7 | c.3519C>T | p.Cys1173= | synonymous_variant | 21/34 | 1 | NM_024408.4 | P1 | |
NOTCH2 | ENST00000478864.1 | n.179C>T | non_coding_transcript_exon_variant | 1/2 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00244 AC: 372AN: 152186Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00145 AC: 364AN: 251312Hom.: 1 AF XY: 0.00134 AC XY: 182AN XY: 135844
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GnomAD4 exome AF: 0.000815 AC: 1190AN: 1460806Hom.: 11 Cov.: 32 AF XY: 0.000837 AC XY: 608AN XY: 726734
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GnomAD4 genome ? AF: 0.00243 AC: 370AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.00251 AC XY: 187AN XY: 74476
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 04, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | NOTCH2: BP4, BP7 - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 15, 2016 | - - |
Hajdu-Cheney syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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