rs764599897
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_005188.4(CBL):c.1423G>A(p.Gly475Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G475V) has been classified as Uncertain significance.
Frequency
Consequence
NM_005188.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBL | NM_005188.4 | c.1423G>A | p.Gly475Ser | missense_variant | 9/16 | ENST00000264033.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBL | ENST00000264033.6 | c.1423G>A | p.Gly475Ser | missense_variant | 9/16 | 1 | NM_005188.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250944Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135674
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461654Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727156
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74320
ClinVar
Submissions by phenotype
Juvenile myelomonocytic leukemia;C3150803:CBL-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 03, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 30, 2023 | Variant summary: CBL c.1423G>A (p.Gly475Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250944 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1423G>A in individuals affected with Noonan Syndrome-Like Disorder and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27069254, 25224413, 19387008, 23690417, 21828135, 19901108, 20619386, 25952305, 20951944, 19620960, 22733026, 23010802, 29296819). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely benign, and one as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
RASopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Apr 04, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at