18-23237228-A-G

Variant names:

• chr18-23237228-A-G
• NM_001100619.3:c.1429A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001100619.3(CABLES1):​c.1429A>G​(p.Ile477Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CABLES1 NM_001100619.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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]

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]

ACMG classification

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=0.30569136).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CABLES1	NM_001100619.3	c.1429A>G	p.Ile477Val	missense_variant	Exon 7 of 10	ENST00000256925.12	NP_001094089.1
CABLES1	NM_138375.3	c.634A>G	p.Ile212Val	missense_variant	Exon 7 of 10		NP_612384.1
CABLES1	NM_001256438.1	c.448A>G	p.Ile150Val	missense_variant	Exon 7 of 10		NP_001243367.1
CABLES1	NR_023359.2	n.332-15732A>G		intron_variant	Intron 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CABLES1	ENST00000256925.12	c.1429A>G	p.Ile477Val	missense_variant	Exon 7 of 10	1	NM_001100619.3	ENSP00000256925.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1429A>G (p.I477V) alteration is located in exon 7 (coding exon 7) of the CABLES1 gene. This alteration results from a A to G substitution at nucleotide position 1429, causing the isoleucine (I) at amino acid position 477 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	0.28
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.084	.;T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.2	.;M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.42	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.083	T;T;T
Sift4G	Benign	0.93	T;T;T
Polyphen		0.26, 0.037	.;B;B
Vest4		0.50
MutPred		0.46		.;Loss of catalytic residue at P479 (P = 0.0289);.;
MVP		0.45
MPC		0.50
ClinPred		0.80	D
GERP RS		5.8
Varity_R		0.12
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-20817192;