NM_001100619.3:c.1069C>T

Variant names:

• chr18-23214035-C-T
• rs772653223
• NM_001100619.3:c.1069C>T

Variant summary

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

The NM_001100619.3(CABLES1):​c.1069C>T​(p.Arg357Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,612,400 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CABLES1 NM_001100619.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.64
• 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]

TMEM241 (HGNC:31723): (transmembrane protein 241) Predicted to enable antiporter activity. Predicted to be involved in carbohydrate transport and transmembrane transport. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CABLES1	NM_001100619.3	MANE Select	c.1069C>T	p.Arg357Cys	missense	Exon 4 of 10	NP_001094089.1	Q8TDN4-1
	CABLES1	NM_138375.3		c.274C>T	p.Arg92Cys	missense	Exon 4 of 10	NP_612384.1	Q8TDN4-2
	CABLES1	NM_001256438.1		c.88C>T	p.Arg30Cys	missense	Exon 4 of 10	NP_001243367.1	Q8TDN4-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CABLES1	ENST00000256925.12	TSL:1 MANE Select	c.1069C>T	p.Arg357Cys	missense	Exon 4 of 10	ENSP00000256925.7	Q8TDN4-1
	CABLES1	ENST00000420687.2	TSL:1	c.274C>T	p.Arg92Cys	missense	Exon 4 of 10	ENSP00000413851.2	Q8TDN4-2
	CABLES1	ENST00000952329.1		c.976C>T	p.Arg326Cys	missense	Exon 3 of 9	ENSP00000622388.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 249058 AF XY: 0.00000740

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1460148 Hom.: 0 Cov.: 28 AF XY: 0.0000193 AC XY: 14 AN XY: 726492

African (AFR) AF: 0.0000299 AC: 1 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1110806

Other (OTH) AF: 0.0000166 AC: 1 AN: 60330

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74444

African (AFR) AF: 0.0000241 AC: 1 AN: 41530

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.26
Sift	Benign	0.073	T
Sift4G	Benign	0.089	T
Polyphen		1.0	D
Vest4		0.64
MutPred		0.47		Loss of disorder (P = 0.0587)
MVP		0.61
MPC		1.6
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.27
gMVP		0.59
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs772653223; hg19: chr18-20793999;