rs150811339
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_005188.4(CBL):c.2363G>A(p.Arg788Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005188.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CBL | NM_005188.4 | c.2363G>A | p.Arg788Gln | missense_variant | Exon 15 of 16 | ENST00000264033.6 | NP_005179.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000322 AC: 49AN: 152190Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000111 AC: 28AN: 251456Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135904
GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19AN XY: 727238
GnomAD4 genome AF: 0.000322 AC: 49AN: 152308Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23AN XY: 74482
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
DNA sequence analysis of the CBL gene demonstrated a sequence change, c.2363G>A, in exon 15 that results in an amino acid change, p.Arg788Gln. This sequence change has been described in the gnomAD database with a frequency of 0.08% in the African American/African subpopulation (dbSNP rs150811339). The p.Arg788Gln change affects a moderately conserved amino acid residue located in a domain of the CBL protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg788Gln substitution. This sequence change does not appear to have been previously described in patients with CBL-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg788Gln change remains unknown at this time. -
Variant summary: CBL c.2363G>A (p.Arg788Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251456 control chromosomes. The observed variant frequency is approximately 44.54 fold of the estimated maximal expected allele frequency for a pathogenic variant in CBL causing Noonan Syndrome And Related Conditions phenotype (2.5e-06). To our knowledge, no occurrence of c.2363G>A in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 180823). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided Uncertain:1Benign:1
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In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
RASopathy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at