18-23135929-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001100619.3(CABLES1):c.167G>T(p.Arg56Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000208 in 1,107,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CABLES1
NM_001100619.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.19

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]

CABLES1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38286993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CABLES1	NM_001100619.3 linkuse as main transcript	c.167G>T	p.Arg56Leu	missense_variant	1/10	ENST00000256925.12
CABLES1	NM_001256438.1 linkuse as main transcript	c.-137+1259G>T		intron_variant
CABLES1	NR_023359.2 linkuse as main transcript	n.88+1278G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CABLES1	ENST00000256925.12 linkuse as main transcript	c.167G>T	p.Arg56Leu	missense_variant	1/10	1	NM_001100619.3		Q8TDN4-1
CABLES1	ENST00000400473.6 linkuse as main transcript	c.-137+1259G>T		intron_variant		2		P1	Q8TDN4-4
CABLES1	ENST00000580153.5 linkuse as main transcript	c.-221+384G>T		intron_variant		5
CABLES1	ENST00000579963.5 linkuse as main transcript	c.-137+1278G>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000813

AC:

AN:

147522

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000269

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000673

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000115

AC:

AN:

959536

Hom.:

Cov.:

AF XY:

0.0000109

AC XY:

AN XY:

457128

show subpopulations

Gnomad4 AFR exome

AF:

0.000472

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:

0.00000118

Gnomad4 OTH exome

AF:

0.0000292

GnomAD4 genome

AF:

0.0000813

AC:

AN:

147632

Hom.:

Cov.:

AF XY:

0.0000278

AC XY:

AN XY:

71902

show subpopulations

Gnomad4 AFR

AF:

0.000268

Gnomad4 AMR

AF:

0.0000672

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

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

Jan 20, 2023

The c.167G>T (p.R56L) alteration is located in exon 1 (coding exon 1) of the CABLES1 gene. This alteration results from a G to T substitution at nucleotide position 167, causing the arginine (R) at amino acid position 56 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

Uncertain

0.40

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.13

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.56

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.38

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.55

MutationTaster

Benign

1.0

D;N

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-2.1

REVEL

Benign

0.22

Sift

Pathogenic

0.0

Sift4G

Benign

0.085

Polyphen

0.98

Vest4

0.24

MVP

0.61

MPC

1.4

ClinPred

0.79

GERP RS

1.1

Varity_R

0.24

gMVP

0.48

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over