NM_001100619.3:c.1520C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001100619.3(CABLES1):​c.1520C>T​(p.Pro507Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,590 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 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CABLES1
NM_001100619.3 missense

Scores

10
5
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
CABLES1 (HGNC:25097): (Cdk5 and Abl enzyme substrate 1) This gene encodes a protein involved in regulation of the cell cycle through interactions with several cyclin-dependent kinases. One study (PMID: 16177568) reported aberrant splicing of transcripts from this gene which results in removal of the cyclin binding domain only in human cancer cells, and reduction in gene expression was shown in colorectal cancers (PMID: 17982127).Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]
TMEM241 (HGNC:31723): (transmembrane protein 241) Predicted to enable antiporter activity. Predicted to be involved in carbohydrate transport and transmembrane transport. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CABLES1NM_001100619.3 linkc.1520C>T p.Pro507Leu missense_variant Exon 8 of 10 ENST00000256925.12 NP_001094089.1 Q8TDN4-1A7K6Y5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CABLES1ENST00000256925.12 linkc.1520C>T p.Pro507Leu missense_variant Exon 8 of 10 1 NM_001100619.3 ENSP00000256925.7 Q8TDN4-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152162
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000800
AC:
2
AN:
249900
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135490
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000157
AC:
23
AN:
1461428
Hom.:
0
Cov.:
29
AF XY:
0.0000124
AC XY:
9
AN XY:
727050
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:
0.0000198
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152162
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1
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
Jul 11, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1520C>T (p.P507L) alteration is located in exon 8 (coding exon 8) of the CABLES1 gene. This alteration results from a C to T substitution at nucleotide position 1520, causing the proline (P) at amino acid position 507 to be replaced by a leucine (L). 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
0.97
BayesDel_addAF
Uncertain
0.086
D
BayesDel_noAF
Benign
-0.10
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.71
.;D;.
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
1.0
D;D;D
M_CAP
Benign
0.043
D
MetaRNN
Pathogenic
0.84
D;D;D
MetaSVM
Benign
-0.81
T
MutationAssessor
Pathogenic
3.2
.;M;.
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-9.4
D;D;D
REVEL
Uncertain
0.46
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.88, 1.0
.;P;D
Vest4
0.85
MutPred
0.43
.;Gain of catalytic residue at P507 (P = 0.0068);.;
MVP
0.47
MPC
1.4
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.59
gMVP
0.74

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: rs749836137; hg19: chr18-20832997; API