Genetic Variant CABLES1:p.Asp75Asp (chr18-23135987-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_001100619.3(CABLES1):c.225C>T(p.Asp75Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,138,040 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 4 hom. )

Consequence

CABLES1
NM_001100619.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.481

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]

CABLES1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 18-23135987-C-T is Benign according to our data. Variant chr18-23135987-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 779177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.481 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CABLES1	NM_001100619.3 link	c.225C>T	p.Asp75Asp	synonymous_variant	Exon 1 of 10	ENST00000256925.12	NP_001094089.1	Q8TDN4-1A7K6Y5
CABLES1	NM_001256438.1 link	c.-137+1317C>T		intron_variant	Intron 1 of 9		NP_001243367.1	Q8TDN4-4
CABLES1	NR_023359.2 link	n.88+1336C>T		intron_variant	Intron 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CABLES1	ENST00000256925.12 link	c.225C>T	p.Asp75Asp	synonymous_variant	Exon 1 of 10	1	NM_001100619.3	ENSP00000256925.7	Q8TDN4-1
CABLES1	ENST00000400473.6 link	c.-137+1317C>T		intron_variant	Intron 1 of 9	2		ENSP00000383321.2	Q8TDN4-4
CABLES1	ENST00000580153.5 link	c.-221+442C>T		intron_variant	Intron 1 of 3	5		ENSP00000461994.1	A0A0G2JLG8
CABLES1	ENST00000579963.5 link	n.-137+1336C>T		intron_variant	Intron 1 of 6	2		ENSP00000464435.1	J3QRY5

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

212

AN:

148268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000195

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.00147

Gnomad ASJ

AF:

0.000881

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00250

Gnomad OTH

AF:

0.00293

GnomAD3 exomes

AF:

0.00199

AC:

AN:

27112

Hom.:

AF XY:

0.00265

AC XY:

AN XY:

15482

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000441

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00143

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00298

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00225

AC:

2225

AN:

989664

Hom.:

Cov.:

AF XY:

0.00233

AC XY:

1090

AN XY:

468616

show subpopulations

Gnomad4 AFR exome

AF:

0.000198

Gnomad4 AMR exome

AF:

0.00217

Gnomad4 ASJ exome

AF:

0.000401

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000797

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00248

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.00143

AC:

212

AN:

148376

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

72298

show subpopulations

Gnomad4 AFR

AF:

0.000194

Gnomad4 AMR

AF:

0.00147

Gnomad4 ASJ

AF:

0.000881

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00250

Gnomad4 OTH

AF:

0.00290

Alfa

AF:

0.00148

Hom.:

Bravo

AF:

0.00159

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.98

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over