Genetic Variant CACUL1:p.Asp19Tyr (chr10-118754708-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_153810.5(CACUL1):c.55G>T(p.Asp19Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D19N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACUL1
NM_153810.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.47

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

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_153810.5. 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
	CACUL1	NM_153810.5	MANE Select	c.55G>T	p.Asp19Tyr	missense	Exon 1 of 9	NP_722517.3	Q86Y37-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACUL1	ENST00000369151.8	TSL:1 MANE Select	c.55G>T	p.Asp19Tyr	missense	Exon 1 of 9	ENSP00000358147.2	Q86Y37-1
CACUL1	ENST00000493518.5	TSL:1	n.55G>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000431329.1	Q86Y37-2
CACUL1	ENST00000911131.1		c.55G>T	p.Asp19Tyr	missense	Exon 1 of 8	ENSP00000581190.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000125

AC:

AN:

239412

AF XY:

0.0000153

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000895

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000138

AC:

AN:

1454000

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723512

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31992

American (AMR)

AF:

0.0000454

AC:

AN:

44006

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25656

East Asian (EAS)

AF:

0.00

AC:

AN:

38362

South Asian (SAS)

AF:

0.00

AC:

AN:

85746

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109122

Other (OTH)

AF:

0.00

AC:

AN:

60064

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.83

M_CAP

Benign

0.069

MetaRNN

Uncertain

0.67

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.4

PhyloP100

4.5

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-2.2

REVEL

Benign

0.22

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.98

Vest4

0.78

MutPred

0.41

Gain of phosphorylation at D19 (P = 0.023)

MVP

0.52

MPC

1.2

ClinPred

0.91

GERP RS

3.9

PromoterAI

-0.10

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.58

gMVP

0.66

Mutation Taster

=86/14

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over