chr18-23136001-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001100619.3(CABLES1):​c.239C>T​(p.Pro80Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000526 in 1,140,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

CABLES1
NM_001100619.3 missense

Scores

1
1
17

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.255
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.033331126).
BP6
Variant 18-23136001-C-T is Benign according to our data. Variant chr18-23136001-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3136226.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CABLES1NM_001100619.3 linkc.239C>T p.Pro80Leu missense_variant Exon 1 of 10 ENST00000256925.12 NP_001094089.1 Q8TDN4-1A7K6Y5
CABLES1NM_001256438.1 linkc.-137+1331C>T intron_variant Intron 1 of 9 NP_001243367.1 Q8TDN4-4
CABLES1NR_023359.2 linkn.88+1350C>T intron_variant Intron 1 of 6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CABLES1ENST00000256925.12 linkc.239C>T p.Pro80Leu missense_variant Exon 1 of 10 1 NM_001100619.3 ENSP00000256925.7 Q8TDN4-1
CABLES1ENST00000400473.6 linkc.-137+1331C>T intron_variant Intron 1 of 9 2 ENSP00000383321.2 Q8TDN4-4
CABLES1ENST00000580153.5 linkc.-221+456C>T intron_variant Intron 1 of 3 5 ENSP00000461994.1 A0A0G2JLG8
CABLES1ENST00000579963.5 linkn.-137+1350C>T intron_variant Intron 1 of 6 2 ENSP00000464435.1 J3QRY5

Frequencies

GnomAD3 genomes
AF:
0.00000674
AC:
1
AN:
148370
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.000488
GnomAD4 exome
AF:
0.00000504
AC:
5
AN:
992440
Hom.:
0
Cov.:
30
AF XY:
0.00000213
AC XY:
1
AN XY:
469464
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000150
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000595
Gnomad4 SAS exome
AF:
0.0000506
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000232
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000674
AC:
1
AN:
148370
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
72262
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000488
Bravo
AF:
0.0000113
ExAC
AF:
0.0000229
AC:
2

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Dec 14, 2023
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.70
CADD
Benign
14
DANN
Uncertain
0.98
DEOGEN2
Benign
0.017
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.019
N
LIST_S2
Benign
0.56
T
M_CAP
Benign
0.053
D
MetaRNN
Benign
0.033
T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.0
N
PrimateAI
Pathogenic
0.91
D
PROVEAN
Benign
0.57
N
REVEL
Benign
0.037
Sift
Benign
1.0
T
Sift4G
Benign
0.75
T
Polyphen
0.0
B
Vest4
0.050
MutPred
0.34
Loss of catalytic residue at P79 (P = 0.0141);
MVP
0.30
MPC
1.1
ClinPred
0.082
T
GERP RS
-2.4
Varity_R
0.037
gMVP
0.087

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs771528127; hg19: chr18-20715965; API