Genetic Variant CACUL1:p.Asp19Asn (chr10-118754708-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153810.5(CACUL1):c.55G>A(p.Asp19Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000374 in 1,606,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CACUL1
NM_153810.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.47

Variant links:

Genes affected

CACUL1 (HGNC:23727): (CDK2 associated cullin domain 1) Enables protein kinase binding activity. Involved in G1/S transition of mitotic cell cycle; positive regulation of cell population proliferation; and positive regulation of protein kinase activity. [provided by Alliance of Genome Resources, Apr 2022]

CACUL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16589236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACUL1	NM_153810.5 link	c.55G>A	p.Asp19Asn	missense_variant	Exon 1 of 9	ENST00000369151.8	NP_722517.3	Q86Y37-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACUL1	ENST00000369151.8 link	c.55G>A	p.Asp19Asn	missense_variant	Exon 1 of 9	1	NM_153810.5	ENSP00000358147.2	Q86Y37-1
CACUL1	ENST00000493518.5 link	n.55G>A		non_coding_transcript_exon_variant	Exon 1 of 10	1		ENSP00000431329.1	Q86Y37-2
CACUL1	ENST00000477583.1 link	n.-231G>A		upstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

GnomAD3 exomes

AF:

0.00000835

AC:

AN:

239412

Hom.:

AF XY:

0.00000766

AC XY:

AN XY:

130628

show subpopulations

Gnomad AFR exome

AF:

0.000147

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1454000

Hom.:

Cov.:

AF XY:

0.00000553

AC XY:

AN XY:

723512

show subpopulations

Gnomad4 AFR exome

AF:

0.0000625

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.55G>A (p.D19N) alteration is located in exon 1 (coding exon 1) of the CACUL1 gene. This alteration results from a G to A substitution at nucleotide position 55, causing the aspartic acid (D) at amino acid position 19 to be replaced by an asparagine (N). 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

Pathogenic

0.86

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.050

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.0062

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.4

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.3

REVEL

Benign

0.060

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.013

Vest4

0.52

MutPred

0.40

Gain of helix (P = 0.0854);

MVP

0.14

MPC

1.1

ClinPred

0.74

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.53

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