NM_001100619.3:c.919T>A

Variant names:

• chr18-23194449-T-A
• rs11660370
• NM_001100619.3:c.919T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001100619.3(CABLES1):​c.919T>A​(p.Cys307Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CABLES1 NM_001100619.3 missense, splice_region
• Scores: Splicing: ADA: 0.3662
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.44
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001100619.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CABLES1	NM_001100619.3	MANE Select	c.919T>A	p.Cys307Ser	missense splice_region	Exon 3 of 10	NP_001094089.1
	CABLES1	NM_138375.3		c.124T>A	p.Cys42Ser	missense splice_region	Exon 3 of 10	NP_612384.1
	CABLES1	NM_001256438.1		c.-63T>A		splice_region	Exon 3 of 10	NP_001243367.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CABLES1	ENST00000256925.12	TSL:1 MANE Select	c.919T>A	p.Cys307Ser	missense splice_region	Exon 3 of 10	ENSP00000256925.7
	CABLES1	ENST00000420687.2	TSL:1	c.124T>A	p.Cys42Ser	missense splice_region	Exon 3 of 10	ENSP00000413851.2
	CABLES1	ENST00000400473.6	TSL:2	c.-63T>A		splice_region	Exon 3 of 10	ENSP00000383321.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L
PhyloP100		7.4
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.026	D
Sift4G	Benign	0.25	T
Polyphen		1.0	D
Vest4		0.88
MutPred		0.32		Gain of phosphorylation at C307 (P = 0.0022)
MVP		0.64
MPC		2.3
ClinPred		0.96	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.55
Mutation Taster		=204/96	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.37
dbscSNV1_RF	Benign	0.46
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.30		Position offset: -1

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

Other links and lift over

dbSNP: rs11660370; hg19: chr18-20774413;