18-23136103-C-T

Variant names:

• chr18-23136103-C-T
• rs28477404
• NM_001100619.3:c.341C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001100619.3(CABLES1):​c.341C>T​(p.Ala114Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,035,570 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (1 hom.)
• Consequence: CABLES1 NM_001100619.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15245202).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CABLES1	NM_001100619.3	c.341C>T	p.Ala114Val	missense_variant	Exon 1 of 10	ENST00000256925.12	NP_001094089.1
CABLES1	NM_001256438.1	c.-137+1433C>T		intron_variant	Intron 1 of 9		NP_001243367.1
CABLES1	NR_023359.2	n.88+1452C>T		intron_variant	Intron 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CABLES1	ENST00000256925.12	c.341C>T	p.Ala114Val	missense_variant	Exon 1 of 10	1	NM_001100619.3	ENSP00000256925.7
CABLES1	ENST00000400473.6	c.-137+1433C>T		intron_variant	Intron 1 of 9	2		ENSP00000383321.2
CABLES1	ENST00000580153.5	c.-220-421C>T		intron_variant	Intron 1 of 3	5		ENSP00000461994.1
CABLES1	ENST00000579963.5	n.-137+1452C>T		intron_variant	Intron 1 of 6	2		ENSP00000464435.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000212 AC: 22 AN: 1035570 Hom.: 1 Cov.: 32 AF XY: 0.0000163 AC XY: 8 AN XY: 489646

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000454

Gnomad4 SAS exome AF: 0.000712

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000673

Gnomad4 OTH exome AF: 0.0000250

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.341C>T (p.A114V) alteration is located in exon 1 (coding exon 1) of the CABLES1 gene. This alteration results from a C to T substitution at nucleotide position 341, causing the alanine (A) at amino acid position 114 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	0.19
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.052
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.16	T
Polyphen		0.75	P
Vest4		0.087
MutPred		0.32		Gain of MoRF binding (P = 0.1078);
MVP		0.41
MPC		1.1
ClinPred		0.44	T
GERP RS		1.6
Varity_R		0.21
gMVP		0.25

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

Other links and lift over

dbSNP: rs28477404; hg19: chr18-20716067;