18-23135922-A-C

Variant summary

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

The NM_001100619.3(CABLES1):c.160A>C(p.Lys54Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: CABLES1 NM_001100619.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75

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]

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=0.26965702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CABLES1	NM_001100619.3	c.160A>C	p.Lys54Gln	missense_variant	1/10	ENST00000256925.12
CABLES1	NM_001256438.1	c.-137+1252A>C		intron_variant
CABLES1	NR_023359.2	n.88+1271A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CABLES1	ENST00000256925.12	c.160A>C	p.Lys54Gln	missense_variant	1/10	1	NM_001100619.3
CABLES1	ENST00000400473.6	c.-137+1252A>C		intron_variant		2		P1
CABLES1	ENST00000580153.5	c.-221+377A>C		intron_variant		5
CABLES1	ENST00000579963.5	c.-137+1271A>C		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.160A>C (p.K54Q) alteration is located in exon 1 (coding exon 1) of the CABLES1 gene. This alteration results from a A to C substitution at nucleotide position 160, causing the lysine (K) at amino acid position 54 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	0.18
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	20
Dann	Benign	0.95
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.089
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.21	T
Polyphen		0.77	P
Vest4		0.22
MutPred		0.20		Loss of methylation at K54 (P = 0.0022);
MVP		0.69
MPC		1.2
ClinPred		0.62	D
GERP RS		2.0
Varity_R		0.33
gMVP		0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-20715886;