18-23135928-C-T

Variant names:

• chr18-23135928-C-T
• rs751362226
• NM_001100619.3:c.166C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BP6

The NM_001100619.3(CABLES1):​c.166C>T​(p.Arg56Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000094 in 1,106,390 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R56L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: CABLES1 NM_001100619.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.74
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33564955).
• BP6: Variant 18-23135928-C-T is Benign according to our data. Variant chr18-23135928-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3483834.

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.166C>T	p.Arg56Cys	missense	Exon 1 of 10	NP_001094089.1	Q8TDN4-1
	CABLES1	NM_001256438.1		c.-137+1258C>T		intron	N/A	NP_001243367.1	Q8TDN4-4
	CABLES1	NR_023359.2		n.88+1277C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CABLES1	ENST00000256925.12	TSL:1 MANE Select	c.166C>T	p.Arg56Cys	missense	Exon 1 of 10	ENSP00000256925.7	Q8TDN4-1
	CABLES1	ENST00000877774.1		c.166C>T	p.Arg56Cys	missense	Exon 1 of 9	ENSP00000547833.1
	CABLES1	ENST00000952329.1		c.166C>T	p.Arg56Cys	missense	Exon 1 of 9	ENSP00000622388.1

Frequencies

GnomAD3 genomes AF: 0.000156 AC: 23 AN: 147480 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000539

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: 0.000106

Gnomad OTH AF: 0.00147

GnomAD2 exomes AF: 0.0000547 AC: 1 AN: 18270 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00333

GnomAD4 exome AF: 0.0000845 AC: 81 AN: 958798 Hom.: 0 Cov.: 30 AF XY: 0.0000832 AC XY: 38 AN XY: 456722

African (AFR) AF: 0.00 AC: 0 AN: 19024

American (AMR) AF: 0.000355 AC: 2 AN: 5638

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 12078

South Asian (SAS) AF: 0.00 AC: 0 AN: 19764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2278

European-Non Finnish (NFE) AF: 0.0000934 AC: 79 AN: 845950

Other (OTH) AF: 0.00 AC: 0 AN: 34198

GnomAD4 genome AF: 0.000156 AC: 23 AN: 147592 Hom.: 1 Cov.: 32 AF XY: 0.000167 AC XY: 12 AN XY: 71898

African (AFR) AF: 0.000122 AC: 5 AN: 41028

American (AMR) AF: 0.000538 AC: 8 AN: 14866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 5072

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000106 AC: 7 AN: 66214

Other (OTH) AF: 0.00145 AC: 3 AN: 2068

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000212

ExAC AF: 0.0000326 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.076
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.7
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.041	D
Polyphen		1.0	D
Vest4		0.26
MVP		0.66
MPC		1.5
ClinPred		0.22	T
GERP RS		2.0
PromoterAI		0.012	Neutral
Varity_R		0.25
gMVP		0.43
Mutation Taster		=82/18	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: rs751362226; hg19: chr18-20715892;