rs199788586
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_005188.4(CBL):c.2312A>T(p.Asp771Val) variant causes a missense change. The variant allele was found at a frequency of 0.000101 in 1,614,060 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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_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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CBL | NM_005188.4 | c.2312A>T | p.Asp771Val | missense_variant | Exon 15 of 16 | ENST00000264033.6 | NP_005179.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251462Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135904
GnomAD4 exome AF: 0.000101 AC: 148AN: 1461872Hom.: 1 Cov.: 32 AF XY: 0.000106 AC XY: 77AN XY: 727242
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74352
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Variant classified as Uncertain Significance - Favor Benign. The p.Asp771Val var iant in CBL has been identified by our laboratory in 2 Caucasian individuals wit h clinical features of a RASopathy disorder, both of whom also carried a disease -causing variant in another gene sufficient to explain their disease. This varia nt has been identified in 13/66740 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199788586). Computati onal prediction tools and conservation analysis suggest that this variant may no t impact the protein, though this information is not predictive enough to rule o ut pathogenicity. In summary, while the clinical significance of the p.Asp771Val variant is uncertain, the presence of this variant in combination with a report ed pathogenic variant suggests that it is more likely to be benign. -
Variant summary: CBL c.2312A>T (p.Asp771Val) results in a non-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 9.1e-05 in 251462 control chromosomes. The observed variant frequency is approximately 37 fold of the estimated maximal expected allele frequency for a pathogenic variant in CBL causing Noonan Syndrome And Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2312A>T in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory has re-classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
not provided Benign:2
CBL: BP4, BS1 -
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Cardiovascular phenotype Uncertain:1
The c.2312A>T (p.D771V) alteration is located in exon 15 (coding exon 15) of the CBL gene. This alteration results from a A to T substitution at nucleotide position 2312, causing the aspartic acid (D) at amino acid position 771 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Noonan syndrome and Noonan-related syndrome Uncertain:1
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CBL-related disorder Benign:1
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). -
RASopathy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at