18-23235975-C-A

Position:

chr18-23235975-C-A

Variant summary

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

The NM_001100619.3(CABLES1):c.1266C>A(p.Phe422Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000743 in 1,614,130 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 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CABLES1
NM_001100619.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.57

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:

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]

TMEM241 links:

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=0.17464498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CABLES1	NM_001100619.3 link	c.1266C>A	p.Phe422Leu	missense_variant	6/10	ENST00000256925.12	NP_001094089.1	Q8TDN4-1A7K6Y5
CABLES1	NM_138375.3 link	c.471C>A	p.Phe157Leu	missense_variant	6/10		NP_612384.1	Q8TDN4-2A0A024RC20
CABLES1	NM_001256438.1 link	c.285C>A	p.Phe95Leu	missense_variant	6/10		NP_001243367.1	Q8TDN4-4
CABLES1	NR_023359.2 link	n.332-16985C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CABLES1	ENST00000256925.12 link	c.1266C>A	p.Phe422Leu	missense_variant	6/10	1	NM_001100619.3	ENSP00000256925.7		Q8TDN4-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152244

Hom.:

Cov.:

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:

0.000577

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

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

249582

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135408

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000334

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000577

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000331

AC:

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

Nov 08, 2022

The c.1266C>A (p.F422L) alteration is located in exon 6 (coding exon 6) of the CABLES1 gene. This alteration results from a C to A substitution at nucleotide position 1266, causing the phenylalanine (F) at amino acid position 422 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

0.46

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.057

.;T;.

Eigen

Benign

0.0044

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.86

D;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

.;L;.

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.75

T;T;T

Sift4G

Benign

0.76

T;T;T

Polyphen

0.99, 0.012

.;D;B

Vest4

0.59

MutPred

0.20

.;Gain of MoRF binding (P = 0.1252);.;

MVP

0.36

MPC

1.0

ClinPred

0.22

GERP RS

4.6

Varity_R

0.45

gMVP

0.34

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