18-23235944-G-A

Variant names:

• chr18-23235944-G-A
• rs373572190
• NM_001100619.3:c.1235G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001100619.3(CABLES1):​c.1235G>A​(p.Arg412Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CABLES1 NM_001100619.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.57

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CABLES1	NM_001100619.3	c.1235G>A	p.Arg412Gln	missense_variant	Exon 6 of 10	ENST00000256925.12	NP_001094089.1
CABLES1	NM_138375.3	c.440G>A	p.Arg147Gln	missense_variant	Exon 6 of 10		NP_612384.1
CABLES1	NM_001256438.1	c.254G>A	p.Arg85Gln	missense_variant	Exon 6 of 10		NP_001243367.1
CABLES1	NR_023359.2	n.332-17016G>A		intron_variant	Intron 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CABLES1	ENST00000256925.12	c.1235G>A	p.Arg412Gln	missense_variant	Exon 6 of 10	1	NM_001100619.3	ENSP00000256925.7

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000601 AC: 15 AN: 249582 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135408

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS 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: 0.0000267 AC: 39 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74328

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000172 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.000265 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1235G>A (p.R412Q) alteration is located in exon 6 (coding exon 6) of the CABLES1 gene. This alteration results from a G to A substitution at nucleotide position 1235, causing the arginine (R) at amino acid position 412 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.073	.;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.1	.;L;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.99	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.17	T;D;T
Sift4G	Benign	0.45	T;T;T
Polyphen		1.0, 1.0	.;D;D
Vest4		0.76
MVP		0.65
MPC		1.5
ClinPred		0.47	T
GERP RS		5.5
Varity_R		0.42
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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

Other links and lift over

dbSNP: rs373572190; hg19: chr18-20815908;