7-107749020-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_024814.4(CBLL1):​c.154C>T​(p.Pro52Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

CBLL1
NM_024814.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.50
Variant links:
Genes affected
CBLL1 (HGNC:21225): (Cbl proto-oncogene like 1) This gene encodes an E3 ubiquitin-ligase for the E-cadherin complex and mediates its ubiquitination, endocytosis, and degradation in the lysosomes. The encoded protein contains a RING-finger domain and is also thought to have a role in control of cell proliferation. A related pseudogene has been identified on chromosome X. Alternative splicing results in a non-coding transcript variant. [provided by RefSeq, Aug 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.11198062).
BS2
High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CBLL1NM_024814.4 linkc.154C>T p.Pro52Ser missense_variant Exon 2 of 6 ENST00000440859.8 NP_079090.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CBLL1ENST00000440859.8 linkc.154C>T p.Pro52Ser missense_variant Exon 2 of 6 1 NM_024814.4 ENSP00000401277.2 Q75N03-1

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152200
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000756
AC:
19
AN:
251294
Hom.:
0
AF XY:
0.0000883
AC XY:
12
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000232
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000968
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000486
AC:
71
AN:
1461734
Hom.:
0
Cov.:
30
AF XY:
0.0000509
AC XY:
37
AN XY:
727156
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000246
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:
0.0000459
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152200
Hom.:
0
Cov.:
33
AF XY:
0.000121
AC XY:
9
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000987
Hom.:
0
Bravo
AF:
0.000181
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.000273
EpiControl
AF:
0.000356

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jun 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.154C>T (p.P52S) alteration is located in exon 2 (coding exon 2) of the CBLL1 gene. This alteration results from a C to T substitution at nucleotide position 154, causing the proline (P) at amino acid position 52 to be replaced by a serine (S). 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
Benign
0.10
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T;.;T;T
Eigen
Benign
0.046
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.85
T;T;D;T
M_CAP
Benign
0.0084
T
MetaRNN
Benign
0.11
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L;L;.;.
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-2.6
D;N;.;N
REVEL
Benign
0.060
Sift
Benign
0.12
T;T;.;T
Sift4G
Benign
0.20
T;T;T;T
Polyphen
0.0040
B;.;.;.
Vest4
0.22
MutPred
0.32
Gain of phosphorylation at P52 (P = 0.0174);Gain of phosphorylation at P52 (P = 0.0174);Gain of phosphorylation at P52 (P = 0.0174);.;
MVP
0.41
MPC
0.34
ClinPred
0.072
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.29
gMVP
0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs756977401; hg19: chr7-107389465; API