18-23135929-G-A

Variant names:

• chr18-23135929-G-A
• rs868512083
• NM_001100619.3:c.167G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001100619.3(CABLES1):​c.167G>A​(p.Arg56His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 959,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R56C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CABLES1 NM_001100619.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.19
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34671474).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CABLES1	NM_001100619.3	MANE Select	c.167G>A	p.Arg56His	missense	Exon 1 of 10	NP_001094089.1	Q8TDN4-1
	CABLES1	NM_001256438.1		c.-137+1259G>A		intron	N/A	NP_001243367.1	Q8TDN4-4
	CABLES1	NR_023359.2		n.88+1278G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CABLES1	ENST00000256925.12	TSL:1 MANE Select	c.167G>A	p.Arg56His	missense	Exon 1 of 10	ENSP00000256925.7	Q8TDN4-1
	CABLES1	ENST00000877774.1		c.167G>A	p.Arg56His	missense	Exon 1 of 9	ENSP00000547833.1
	CABLES1	ENST00000952329.1		c.167G>A	p.Arg56His	missense	Exon 1 of 9	ENSP00000622388.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000208 AC: 2 AN: 959536 Hom.: 0 Cov.: 30 AF XY: 0.00000219 AC XY: 1 AN XY: 457128

African (AFR) AF: 0.00 AC: 0 AN: 19050

American (AMR) AF: 0.00 AC: 0 AN: 5690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8536

East Asian (EAS) AF: 0.00 AC: 0 AN: 12156

South Asian (SAS) AF: 0.00 AC: 0 AN: 19800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2288

European-Non Finnish (NFE) AF: 0.00000236 AC: 2 AN: 846360

Other (OTH) AF: 0.00 AC: 0 AN: 34232

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.2
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.056	T
Polyphen		1.0	D
Vest4		0.17
MutPred		0.15		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.68
MPC		1.4
ClinPred		0.74	D
GERP RS		1.1
PromoterAI		-0.046	Neutral
Varity_R		0.20
gMVP		0.41
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs868512083; hg19: chr18-20715893;