Genetic Variant CABLES1:p.Arg56Leu (chr18-23135929-G-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R56C) has been classified as Likely benign.

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

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001100619.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CABLES1	NM_001100619.3	MANE Select	c.167G>T	p.Arg56Leu	missense	Exon 1 of 10	NP_001094089.1	Q8TDN4-1
CABLES1	NM_001256438.1		c.-137+1259G>T		intron	N/A	NP_001243367.1	Q8TDN4-4
CABLES1	NR_023359.2		n.88+1278G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CABLES1	ENST00000256925.12	TSL:1 MANE Select	c.167G>T	p.Arg56Leu	missense	Exon 1 of 10	ENSP00000256925.7	Q8TDN4-1
CABLES1	ENST00000877774.1		c.167G>T	p.Arg56Leu	missense	Exon 1 of 9	ENSP00000547833.1
CABLES1	ENST00000952329.1		c.167G>T	p.Arg56Leu	missense	Exon 1 of 9	ENSP00000622388.1

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

African (AFR)

AF:

0.000472

AC:

AN:

19050

American (AMR)

AF:

0.00

AC:

AN:

5690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8536

East Asian (EAS)

AF:

0.00

AC:

AN:

12156

South Asian (SAS)

AF:

0.00

AC:

AN:

19800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

11424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2288

European-Non Finnish (NFE)

AF:

0.00000118

AC:

AN:

846360

Other (OTH)

AF:

0.0000292

AC:

AN:

34232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000813

AC:

AN:

147632

Hom.:

Cov.:

AF XY:

0.0000278

AC XY:

AN XY:

71902

show subpopulations

African (AFR)

AF:

0.000268

AC:

AN:

41038

American (AMR)

AF:

0.0000672

AC:

AN:

14874

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3400

East Asian (EAS)

AF:

0.00

AC:

AN:

5082

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66228

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000604

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

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

PhyloP100

3.2

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

PromoterAI

0.045

Neutral

(source)

Varity_R

0.24

gMVP

0.48

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over