19-44784397-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_012116.4(CBLC):c.913G>A(p.Gly305Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,576,420 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: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
CBLC
NM_012116.4 missense
NM_012116.4 missense
Scores
5
10
3
Clinical Significance
Conservation
PhyloP100: 9.51
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, 0.974
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBLC | NM_012116.4 | c.913G>A | p.Gly305Ser | missense_variant | 5/11 | ENST00000647358.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBLC | ENST00000647358.2 | c.913G>A | p.Gly305Ser | missense_variant | 5/11 | NM_012116.4 | P1 | ||
CBLC | ENST00000341505.4 | c.779+1906G>A | intron_variant | 1 | |||||
CBLC | ENST00000647063.1 | c.541G>A | p.Gly181Ser | missense_variant, NMD_transcript_variant | 4/6 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152206Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000725 AC: 18AN: 248324Hom.: 0 AF XY: 0.0000745 AC XY: 10AN XY: 134304
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GnomAD4 exome AF: 0.000124 AC: 177AN: 1424214Hom.: 0 Cov.: 31 AF XY: 0.000129 AC XY: 91AN XY: 703434
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GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74362
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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 | Dec 01, 2022 | The c.913G>A (p.G305S) alteration is located in exon 5 (coding exon 5) of the CBLC gene. This alteration results from a G to A substitution at nucleotide position 913, causing the glycine (G) at amino acid position 305 to be replaced by a serine (S). 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
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Uncertain
D;.
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at