19-44778053-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_012116.4(CBLC):c.122C>G(p.Pro41Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 1,456,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000076 ( 0 hom. )
Consequence
CBLC
NM_012116.4 missense
NM_012116.4 missense
Scores
8
8
2
Clinical Significance
Conservation
PhyloP100: 2.34
Genes affected
CBLC (HGNC:15961): (Cbl proto-oncogene C) This gene encodes a member of the Cbl family of E3 ubiquitin ligases. Cbl proteins play important roles in cell signaling through the ubiquitination and subsequent downregulation of tyrosine kinases. Expression of this gene may be restricted to epithelial cells, and alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.945
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBLC | NM_012116.4 | c.122C>G | p.Pro41Arg | missense_variant | 1/11 | ENST00000647358.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBLC | ENST00000647358.2 | c.122C>G | p.Pro41Arg | missense_variant | 1/11 | NM_012116.4 | P1 | ||
CBLC | ENST00000341505.4 | c.122C>G | p.Pro41Arg | missense_variant | 1/10 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome AF: 0.00000755 AC: 11AN: 1456788Hom.: 0 Cov.: 32 AF XY: 0.00000552 AC XY: 4AN XY: 724942
GnomAD4 exome
AF:
AC:
11
AN:
1456788
Hom.:
Cov.:
32
AF XY:
AC XY:
4
AN XY:
724942
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 09, 2022 | The c.122C>G (p.P41R) alteration is located in exon 1 (coding exon 1) of the CBLC gene. This alteration results from a C to G substitution at nucleotide position 122, causing the proline (P) at amino acid position 41 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Pathogenic
D;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.
Sift4G
Uncertain
D;D;.
Polyphen
D;D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0045);Gain of MoRF binding (P = 0.0045);Gain of MoRF binding (P = 0.0045);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at