18-23235944-G-A

Position:

chr18-23235944-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001100619.3(CABLES1):c.1235G>A(p.Arg412Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

CABLES1
NM_001100619.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.57

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:):

TMEM241 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CABLES1	NM_001100619.3 linkuse as main transcript	c.1235G>A	p.Arg412Gln	missense_variant	6/10	ENST00000256925.12	NP_001094089.1	Q8TDN4-1A7K6Y5
CABLES1	NM_138375.3 linkuse as main transcript	c.440G>A	p.Arg147Gln	missense_variant	6/10		NP_612384.1	Q8TDN4-2A0A024RC20
CABLES1	NM_001256438.1 linkuse as main transcript	c.254G>A	p.Arg85Gln	missense_variant	6/10		NP_001243367.1	Q8TDN4-4
CABLES1	NR_023359.2 linkuse as main transcript	n.332-17016G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CABLES1	ENST00000256925.12 linkuse as main transcript	c.1235G>A	p.Arg412Gln	missense_variant	6/10	1	NM_001100619.3	ENSP00000256925.7		Q8TDN4-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000479

GnomAD3 exomes

AF:

0.0000601

AC:

AN:

249582

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135408

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000131

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:

0.000479

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.000265

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000331

AC:

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2021

The c.1235G>A (p.R412Q) alteration is located in exon 6 (coding exon 6) of the CABLES1 gene. This alteration results from a G to A substitution at nucleotide position 1235, causing the arginine (R) at amino acid position 412 to be replaced by a glutamine (Q). 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

0.12

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.073

.;T;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.56

D;D;D

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.1

.;L;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.99

N;N;N

REVEL

Benign

0.28

Sift

Benign

0.17

T;D;T

Sift4G

Benign

0.45

T;T;T

Polyphen

1.0, 1.0

.;D;D

Vest4

0.76

MVP

0.65

MPC

1.5

ClinPred

0.47

GERP RS

5.5

Varity_R

0.42

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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