19-44781296-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_012116.4(CBLC):​c.590C>T​(p.Thr197Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,252 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: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CBLC
NM_012116.4 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.62
Variant links:
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]

Genome browser will be placed here

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, 0.968

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CBLCNM_012116.4 linkc.590C>T p.Thr197Ile missense_variant Exon 3 of 11 ENST00000647358.2 NP_036248.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CBLCENST00000647358.2 linkc.590C>T p.Thr197Ile missense_variant Exon 3 of 11 NM_012116.4 ENSP00000494162.1 Q9ULV8-1
CBLCENST00000341505.4 linkc.590C>T p.Thr197Ile missense_variant Exon 3 of 10 1 ENSP00000340250.4 Q9ULV8-2
CBLCENST00000647063.1 linkn.215C>T non_coding_transcript_exon_variant Exon 2 of 6 ENSP00000495258.1 A0A2R8Y647

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461252
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726960
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 19, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.590C>T (p.T197I) alteration is located in exon 3 (coding exon 3) of the CBLC gene. This alteration results from a C to T substitution at nucleotide position 590, causing the threonine (T) at amino acid position 197 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D;.;D
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.89
.;D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Pathogenic
0.85
D
MutationAssessor
Pathogenic
3.1
M;M;M
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-5.7
D;D;.
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
D;D;.
Sift4G
Pathogenic
0.0010
D;D;.
Polyphen
1.0
D;D;D
Vest4
0.93
MutPred
0.78
Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);
MVP
0.94
MPC
1.0
ClinPred
1.0
D
GERP RS
3.8
Varity_R
0.56
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-45284553; API