18-23136103-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001100619.3(CABLES1):​c.341C>T​(p.Ala114Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,035,570 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000021 ( 1 hom. )

Consequence

CABLES1
NM_001100619.3 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.08
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15245202).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CABLES1NM_001100619.3 linkc.341C>T p.Ala114Val missense_variant Exon 1 of 10 ENST00000256925.12 NP_001094089.1 Q8TDN4-1A7K6Y5
CABLES1NM_001256438.1 linkc.-137+1433C>T intron_variant Intron 1 of 9 NP_001243367.1 Q8TDN4-4
CABLES1NR_023359.2 linkn.88+1452C>T intron_variant Intron 1 of 6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CABLES1ENST00000256925.12 linkc.341C>T p.Ala114Val missense_variant Exon 1 of 10 1 NM_001100619.3 ENSP00000256925.7 Q8TDN4-1
CABLES1ENST00000400473.6 linkc.-137+1433C>T intron_variant Intron 1 of 9 2 ENSP00000383321.2 Q8TDN4-4
CABLES1ENST00000580153.5 linkc.-220-421C>T intron_variant Intron 1 of 3 5 ENSP00000461994.1 A0A0G2JLG8
CABLES1ENST00000579963.5 linkn.-137+1452C>T intron_variant Intron 1 of 6 2 ENSP00000464435.1 J3QRY5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.0000212
AC:
22
AN:
1035570
Hom.:
1
Cov.:
32
AF XY:
0.0000163
AC XY:
8
AN XY:
489646
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000454
Gnomad4 SAS exome
AF:
0.000712
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000673
Gnomad4 OTH exome
AF:
0.0000250
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 21, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.341C>T (p.A114V) alteration is located in exon 1 (coding exon 1) of the CABLES1 gene. This alteration results from a C to T substitution at nucleotide position 341, causing the alanine (A) at amino acid position 114 to be replaced by a valine (V). 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
0.19
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.056
T
Eigen
Benign
-0.44
Eigen_PC
Benign
-0.52
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.50
T
M_CAP
Benign
0.071
D
MetaRNN
Benign
0.15
T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.55
N
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-0.89
N
REVEL
Benign
0.052
Sift
Pathogenic
0.0
D
Sift4G
Benign
0.16
T
Polyphen
0.75
P
Vest4
0.087
MutPred
0.32
Gain of MoRF binding (P = 0.1078);
MVP
0.41
MPC
1.1
ClinPred
0.44
T
GERP RS
1.6
Varity_R
0.21
gMVP
0.25

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: rs28477404; hg19: chr18-20716067; API