1-119963685-C-T
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_024408.4(NOTCH2):c.1804G>A(p.Ala602Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000482 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024408.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NOTCH2 | ENST00000256646.7 | c.1804G>A | p.Ala602Thr | missense_variant | 11/34 | 1 | NM_024408.4 | ENSP00000256646.2 | ||
NOTCH2 | ENST00000479412.2 | n.1942G>A | non_coding_transcript_exon_variant | 10/14 | 1 | |||||
NOTCH2 | ENST00000640021.1 | n.*928G>A | non_coding_transcript_exon_variant | 8/12 | 5 | ENSP00000492223.1 | ||||
NOTCH2 | ENST00000640021.1 | n.*928G>A | 3_prime_UTR_variant | 8/12 | 5 | ENSP00000492223.1 |
Frequencies
GnomAD3 genomes AF: 0.000368 AC: 56AN: 152154Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000283 AC: 71AN: 251102Hom.: 0 AF XY: 0.000251 AC XY: 34AN XY: 135688
GnomAD4 exome AF: 0.000494 AC: 722AN: 1461812Hom.: 0 Cov.: 32 AF XY: 0.000476 AC XY: 346AN XY: 727216
GnomAD4 genome AF: 0.000368 AC: 56AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25AN XY: 74336
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:3
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The NOTCH2 p.Ala602Thr variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs140311741), LOVD 3.0 and in ClinVar (classified as a VUS for Hajdu-Cheney syndrome by Invitae and EGL Genetics). The variant was identified in control databases in 85 of 282500 chromosomes at a frequency of 0.000301 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 78 of 128854 chromosomes (freq: 0.000605), Other in 2 of 7220 chromosomes (freq: 0.000277), African in 2 of 24964 chromosomes (freq: 0.00008), Latino in 2 of 35430 chromosomes (freq: 0.000056) and European (Finnish) in 1 of 25124 chromosomes (freq: 0.00004); it was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Ala602 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jul 28, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 22, 2018 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Hajdu-Cheney syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2023 | - - |
NOTCH2-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 04, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at