18-23136073-C-G

Variant names:

• chr18-23136073-C-G
• rs920622592
• NM_001100619.3:c.311C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001100619.3(CABLES1):​c.311C>G​(p.Ala104Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000067 in 149,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A104V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
• Consequence: CABLES1 NM_001100619.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.412
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04845172).

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.311C>G	p.Ala104Gly	missense	Exon 1 of 10	NP_001094089.1	Q8TDN4-1
	CABLES1	NM_001256438.1		c.-137+1403C>G		intron	N/A	NP_001243367.1	Q8TDN4-4
	CABLES1	NR_023359.2		n.88+1422C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CABLES1	ENST00000256925.12	TSL:1 MANE Select	c.311C>G	p.Ala104Gly	missense	Exon 1 of 10	ENSP00000256925.7	Q8TDN4-1
	CABLES1	ENST00000877774.1		c.311C>G	p.Ala104Gly	missense	Exon 1 of 9	ENSP00000547833.1
	CABLES1	ENST00000952329.1		c.311C>G	p.Ala104Gly	missense	Exon 1 of 9	ENSP00000622388.1

Frequencies

GnomAD3 genomes AF: 0.00000670 AC: 1 AN: 149294 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000670 AC: 1 AN: 149294 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72776

African (AFR) AF: 0.0000243 AC: 1 AN: 41106

American (AMR) AF: 0.00 AC: 0 AN: 15016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66964

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.41
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.033
Sift	Benign	0.27	T
Sift4G	Benign	0.50	T
Polyphen		0.0070	B
Vest4		0.088
MutPred		0.26		Loss of helix (P = 0.0444)
MVP		0.33
MPC		1.1
ClinPred		0.19	T
GERP RS		-0.50
PromoterAI		0.045	Neutral
Varity_R		0.047
gMVP		0.23
Mutation Taster		=96/4	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: rs920622592; hg19: chr18-20716037;